AMPK-Activating Heterocycloalkyloxy(Hetero)Aryl Carboxamide, Sulfonamide And Amine Compounds And Methods For Using The Same

ABSTRACT

Disclosed are carboxamide, sulfonamide and amine compounds, as well as pharmaceutical compositions and methods of use. One embodiment is a compound having the structure 
     
       
         
         
             
             
         
       
     
     in which R 1 , R 2 , R 4 , E, T, n and x are as described herein. In certain embodiments, a compound disclosed herein activates the AMPK pathway, and can be used to treat metabolism-related disorders and conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/348,380, filed Jan. 11, 2012, now U.S. Pat. No. 8,569,340, which is acontinuation of U.S. patent application Ser. No. 12/272,581, now U.S.Pat. No. 8,119,809, filed Nov. 17, 2008, which claims the benefit of theearlier filing dates of U.S. Provisional Patent Application Ser. No.60/988,721, filed Nov. 16, 2007; Ser. No. 60/990,554, filed Nov. 27,2007; Ser. No. 60/990,558, filed Nov. 27, 2007; Ser. No. 60/991,189,filed Nov. 29, 2007; and Ser. No. 61/013,924, filed Dec. 14, 2007, eachof which is hereby incorporated herein by reference in its entirety.

BACKGROUND

1. Field

This disclosure relates generally to compounds, pharmaceuticalcompositions and methods of use of the compounds and compositionscontaining them. This disclosure relates more particularly to certaincarboxamide, sulfonamide and amine compounds and pharmaceuticalcompositions thereof, and to methods of treating and preventingmetabolic disorders such as type II diabetes, atherosclerosis andcardiovascular disease using certain carboxamide, sulfonamide and aminecompounds.

2. Technical Background

Adiponectin is a protein hormone exclusively expressed in and secretedfrom adipose tissue and is the most abundant adipose-specific protein.Adiponectin has been implicated in the modulation of glucose and lipidmetabolism in insulin-sensitive tissues. Decreased circulatingadiponectin levels have been demonstrated in some insulin-resistantstates, such as obesity and type 2 diabetes mellitus and also inpatients with coronary artery disease, atherosclerosis and hypertension.Adiponectin levels are positively correlated with insulin sensitivity,HDL (high density lipoprotein) levels and insulin stimulated glucosedisposal and inversely correlated with adiposity and glucose, insulinand triglyceride levels. Thiazolidinedione drugs, which enhance insulinsensitivity through activation of the peroxisome proliferator-activatedreceptor-γ, increase endogenous adiponectin production in humans.

Adiponectin binds its receptors in liver and skeletal muscle and therebyactivates the 5′-AMP-activated protein kinase (AMPK) pathway.Adiponectin receptors 1 and 2 are membrane-bound proteins found inskeletal muscle and liver tissue. Being a multi-substrate enzyme, AMPKregulates a variety of metabolic processes, such as glucose transport,glycolysis and lipid metabolism. It acts as a sensor of cellular energyhomeostasis and is activated in response to certain hormones and musclecontraction as well as to intracellular metabolic stress signals such asexercise, ischemia, hypoxia and nutrient deprivation. Once activated,AMPK switches on catabolic pathways (such as fatty acid oxidation andglycolysis) and switches off ATP-consuming pathways (such aslipogenesis). Adiponectin improves insulin sensitivity by directlystimulating glucose uptake in adipocytes and muscle and by increasingfatty acid oxidation in liver and muscle, resulting in reducedcirculating fatty acid levels and reduced intracellular triglyceridecontents. Moreover, adiponectin decreases glycogen concentration byreducing the activity of glycogen synthase. Adiponectin also plays aprotective role against inflammation and atherosclerosis. It suppressesthe expression of adhesion molecules in vascular endothelial cells andcytokine production from macrophages, thus inhibiting the inflammatoryprocesses that occur during the early phases of atherosclerosis. What isneeded are compounds, pharmaceutical compositions and methods of usingthem to treat disease states associated with circulating adiponectinlevels, such as type II diabetes, atherosclerosis and cardiovasculardisease.

SUMMARY

Disclosed herein are compounds having structural formula (I)

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, orN-oxide thereof, wherein

-   -   “B” represents -(aryl or heteroaryl)- substituted by w R³ and k        R¹⁴;    -   E is —C(O)—, —S(O)₂— or a single bond;    -   R¹ is H, —(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄ alkyl);    -   R² is -Hca, -Cak-N(R⁹)-G-R²² or —(C₂-C₈ alkyl)-N(R⁹)—R²⁴ in        which one or two carbons of the (C₂-C₈ alkyl) are optionally        replaced by —O—, —S— or —N(R⁹)— and R²⁴ is —R²³, -G-R²³, or        —C(O)O—(C₁-C₆ alkyl);    -   each R³ is substituted on a benzo or pyrido carbon of the ring        system denoted by “B” and is independently selected from —(C₁-C₆        alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆        alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆        alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆        alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and        —CN;    -   w is 0, 1, 2 or 3;    -   each R¹⁴ is substituted on a non-benzo, non pyrido carbon of the        ring system denoted by “B”, and is independently selected from        —(C₁-C₆ alkyl), —(C₁-C₆ halooalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆        alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆        alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆        alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and        —CN;    -   k is 0, 1 or 2;    -   each R⁴ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R⁴ on        the same carbon optionally combine to form oxo;    -   x is 0, 1, 2, 3 or 4;    -   n is 0, 1, 2 or 3;    -   T is —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆        alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰        or

in which

-   -   Q is —(C₀-C₃ alkyl)-, in which each carbon of the —(C₀-C₃        alkyl)- is optionally and independently substituted with one or        two R¹⁶, or —S(O)₂—;    -   the ring system denoted by “A” is heteroaryl, aryl, cycloalkyl        or heterocycloalkyl;    -   each R⁵ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN; and    -   y is 0, 1, 2, 3 or 4;        in which    -   each L is independently selected from —NR⁹C(O)O—, —OC(O)NR⁹—,        —NR⁹C(O)—NR⁹—, —NR⁹C(O)S—, —SC(O)NR⁹—, —NR⁹C(O)—, —C(O)—NR⁹—,        —NR⁹C(S)O—, —OC(S)NR⁹—, —NR⁹C(S)—NR⁹—, —NR⁹C(S)S—, —SC(S)NR⁹—,        —NR⁹C(S)—, —C(S)NR⁹—, —SC(O)NR⁹—, —NR⁹C(S)—, —S(O)₀₋₂—, —C(O)O,        —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—,        —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—,        —NR⁹C(NR²)NR⁹—, —NR⁹SO₂—, —SO₂NR⁹— and —NR⁹SO₂NR⁹—,    -   each R⁶, R⁷, R⁸ and R¹⁰ is independently selected from H,        —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆        alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆        alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹—(C₀-C₆ alkyl),        —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆        alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl),    -   each R⁹ is independently selected from —H, —(C₁-C₄ alkyl) and        —C(O)O—(C₁-C₄ alkyl),    -   each G is independently —(C₀-C₃ alkyl)-, in which each carbon of        the —(C₀-C₃ alkyl)- is optionally and independently substituted        with one or two R¹⁶, or —S(O)₂—,    -   each R¹⁶ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and        optionally two of R¹⁶ on the same carbon combine to form oxo,    -   each R²⁰, R²² and R²³ is independently Ar or Het,    -   each Ar is an optionally substituted aryl,    -   each Het is an optionally substituted heteroaryl,    -   each Cak is an optionally substituted cycloalkyl,    -   each Hca is an optionally substituted heterocycloalkyl, and    -   each alkyl is optionally substituted.

Also disclosed herein are pharmaceutical compositions. Examples of suchcompositions include those having at least one pharmaceuticallyacceptable carrier, diluent or excipient; and a compound,pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxidedescribed above.

Another aspect of the present disclosure includes methods for modulatingmetabolism in subjects. Accordingly, also disclosed are methods fortreating metabolic disorders using the presently disclosed compounds andpharmaceutical compositions.

DETAILED DESCRIPTION

One aspect of the disclosure provides compounds having structuralformula (I):

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, andN-oxides thereof, in which

-   -   “B” represents -(aryl or heteroaryl)- substituted by w R³ and k        R¹⁴;    -   E is —C(O)—, —S(O)₂— or a single bond, provided that when “B” is        phenyl, E is not —C(O)—;    -   R¹ is H, —(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄ alkyl);    -   R² is -Hca, -Cak-N(R⁹)-G-R²² or —(C₂-C₈ alkyl)-N(R⁹)—R²⁴ in        which one or two carbons of the (C₂-C₈ alkyl) are optionally        replaced by —O—, —S— or —N(R⁹)— and R²⁴ is —R²³, -G-R²³, or        —C(O)O—(C₁-C₆ alkyl);    -   each R³ is substituted on a benzo or pyrido carbon of the ring        system denoted by “B” and is independently selected from —(C₁-C₆        alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆        alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆        alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆        alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and        —CN;    -   w is 0, 1, 2 or 3;    -   each R¹⁴ is substituted on a non-benzo, non-pyrido carbon of the        ring system denoted by “B”, and is independently selected from        —(C₁-C₆ alkyl), —(C₁-C₆ halooalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆        alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆        alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆        alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and        —CN;    -   k is 0, 1 or 2;    -   each R⁴ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R⁴ on        the same carbon optionally combine to form oxo;    -   x is 0, 1, 2, 3 or 4;    -   n is 0, 1, 2 or 3;    -   T is —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆        alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰        or

in which

-   -   Q is —(C₀-C₃ alkyl)-, in which each carbon of the —(C₀-C₃        alkyl)- is optionally and independently substituted with one or        two R¹⁶, or —S(O)₂—;    -   the ring system denoted by “A” is heteroaryl, aryl, cycloalkyl        or heterocycloalkyl;    -   each R⁵ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, -halogen,        —NO₂ and —CN; and    -   y is 0, 1, 2, 3 or 4;        in which    -   each L is independently selected from —NR⁹C(O)O—, —OC(O)NR⁹—,        —NR⁹C(O)—NR⁹—, —NR⁹C(O)S—, —SC(O)NR⁹—, —NR⁹C(O)—, —C(O)—NR⁹—,        —NR⁹C(S)O—, —OC(S)NR⁹—, —NR⁹C(S)—NR⁹—, —NR⁹C(S)S—, —SC(S)NR⁹—,        —NR⁹C(S)—, —C(S)NR⁹—, —SC(O)NR⁹—, —NR⁹C(S)—, —S(O)₀₋₂—, —C(O)O,        —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—,        —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—,        —NR⁹C(NR²)NR⁹—, —NR⁹SO₂—, —SO₂NR⁹— and —NR⁹SO₂NR⁹—,    -   each R⁶, R⁷, R⁸ and R¹⁰ is independently selected from H,        —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆        alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆        alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹—(C₀-C₆ alkyl),        —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆        alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl),    -   each R⁹ is independently selected from —H, —(C₁-C₄ alkyl) and        —C(O)O—(C₁-C₄ alkyl),    -   each G is independently —(C₀-C₃ alkyl)-, in which each carbon of        the —(C₀-C₃ alkyl)- is optionally and independently substituted        with one or two R¹⁶, or —S(O)₂—,    -   each R¹⁶ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and        optionally two of R¹⁶ on the same carbon combine to form oxo,    -   each R²⁰, R²² and R²³ is independently Ar or Het,    -   each Ar is an optionally substituted aryl,    -   each Het is an optionally substituted heteroaryl,    -   each Cak is an optionally substituted cycloalkyl,    -   each Hca is an optionally substituted heterocycloalkyl, and    -   each alkyl is optionally substituted.

In certain embodiments of the presently disclosed compounds ofstructural formula (I), the ring system denoted by “B” is

in which X is O or S, and E is —C(O)—. In certain such embodiments, oneR¹⁴ can be substituted on the furano or thieno carbon. In one suchembodiment, R¹⁴ is selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., trifluoromethyl), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹,—(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl), and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in one embodiment, R¹⁴is selected from —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, inwhich each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₂alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), andin which no alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. R¹⁴ canbe, for example, halo (e.g., —Cl or —F), cyano, unsubstituted —(C₁-C₄alkyl) (e.g., methyl or ethyl), or unsubstituted —(C₁-C₄ haloakyl)(e.g., trifluoromethyl). In certain embodiments, R¹⁴ is H or methyl; inothers, R¹⁴ is halo (e.g., Cl). In other embodiments, no R¹⁴ issubstituted on the furano or thieno carbon.

In one embodiment, X is O.

In certain embodiments of the presently disclosed compounds ofstructural formula (I), the ring system denoted by “B” is

and E is —C(O)— or —S(O)₂—.

In certain embodiments of the presently disclosed compounds ofstructural formula (I), the ring system denoted by “B” is

and E is a single bond. In one embodiment, k is 0. In anotherembodiment, k is 1 or 2. In certain embodiments, In each R¹⁴ isindependently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (e.g.,trifluoromethyl), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl), and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in one embodiment, eachR¹⁴ is independently selected from —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl),—(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, inwhich each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₂alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), andin which no alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Each R¹⁴can be, for example, halo (e.g., —Cl or —F), cyano unsubstituted —(C₁-C₄alkyl) (e.g., methyl or ethyl) or unsubstituted —(C₁-C₄ haloakyl) (e.g.,trifluoromethyl).

In certain embodiments of the presently disclosed compounds ofstructural formula (I), T is

In such embodiments, Q is —S(O)₂— or —(C₀-C₃ alkyl)- in which eachcarbon of the (C₀-C₃ alkyl) is optionally and independently substitutedwith one or two R¹⁶, in which each R¹⁶ is independently selected from—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷,—(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,—(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and optionally two ofR¹⁶ on the same carbon combine to form oxo. In certain embodiments, eachR¹⁶ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., trifluoromethyl), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹,—(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, and two R¹⁶ on the same carbon optionallycombine to form an oxo, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl), and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in particular compounds,each R¹⁶ is —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷,—(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰,—(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R¹⁶ on thesame carbon optionally combine to form an oxo, in which each R⁷, R⁸ andR¹⁰ is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkylor haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. In certain embodiments, Q has at mostone R¹⁶ or an oxo substituted thereon. Q can be, for example, anunsubstituted —(C₀-C₃ alkyl)-. In other embodiments, Q is a (C₁-C₃alkyl) having as its only substitution a single oxo group. For example,in certain embodiments, Q is —CH₂—; a single bond; —S(O)₂—; —C(O)—; or—CH(CH₃)—.

In certain embodiments, the

moiety is

for example, p-(trifluoromethyl)phenyl. In other embodiments, the

moiety is

in one such embodiment, Q is a single bond.

The number of substituents on the ring system denoted by “A”, y, is 0,1, 2, 3 or 4. For example, in some embodiments, y is 0, 1, 2 or 3, forexample 1. In one embodiment, y is not zero and at least one R⁵ is halo,cyano, —(C₁-C₄ haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl),—O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl),—C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ or —C(O)—Hca in which the Hcacontains a ring nitrogen atom through which it is bound to the —C(O)—,and in which no alkyl, haloalkyl or heterocycloalkyl is substituted byan aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group.

In certain embodiments of the presently disclosed compounds ofstructural formula (I), each R⁵ is independently selected from —(C₁-C₆alkyl), —(C₁-C₆ haloalkyl) (e.g., trifluoromethyl), —(C₀-C₆ alkyl)-L-R⁷,—(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,—(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸and R¹⁰ is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆haloalkyl) (e.g., trifluoromethyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl),—(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), andin which no alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Forexample, in one embodiment, each R⁵ is —(C₁-C₃ alkyl), —(C₁-C₃haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group.

In one embodiment of the compounds of structural formula (I), y is 0.

In the presently disclosed compounds, the ring system denoted by “A” isheteroaryl, aryl, cycloalkyl or heterocycloalkyl. For example, in oneembodiment, the ring system denoted by “A” is an aryl or a heteroaryl.The ring system denoted by “A” can be, for example, a monocyclic aryl orheteroaryl. In one embodiment, when the “A” ring system is aryl, Q is a—(C₀-C₃ alkyl)- optionally substituted with oxo, and optionallysubstituted with one or more R¹⁶. For example, Q can be a —(C₁-C₃alkyl)- having its only substitution a single oxo, or an unsubstituted—(C₀-C₃ alkyl)-. For example, in certain embodiments, Q is —CH—; asingle bond; —S(O)₂—; —C(O)—; or —CH(CH₃)—.

For example, in certain embodiments of the presently disclosedcompounds, the ring system denoted by “A” is a phenyl. In oneembodiment, y is 1 and R⁵ is attached to the phenyl para to Q. Inanother embodiment, y is 1 and R⁵ is selected from the group consistingof halo, cyano, —(C₁-C₄ haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl),—C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and —C(O)—Hca in which the Hcacontains a ring nitrogen atom through which it is bound to the —C(O)—,and in which no (C₀-C₄ alkyl) or (C₁-C₄ alkyl) is substituted by anaryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group. R⁵can be, for example, —Cl, —F, cyano, —C(O)CH₃, —C(O)OH, —C(O)NH₂,trifluoromethyl, difluoromethyl, difluoromethoxy or trifluoromethoxy. Inanother embodiment, the

moiety is a 3,4-dihalophenyl.

In another embodiment of the presently disclosed compounds of structuralformula (I), the ring system denoted by “A” is a heteroaryl. Forexample, in certain embodiments, the ring system denoted by “A” is apyridyl, a thienyl, or a furanyl. In one embodiment, when the “A” ringsystem is heteroaryl, Q is a —(C₀-C₃ alkyl)- optionally substituted withoxo, and optionally substituted with one or more R¹⁶. For example, Q canbe a —(C₁-C₃ alkyl)- having its only substitution a single oxo, or anunsubstituted —(C₀-C₃ alkyl)-. In certain embodiments, Q is —CH₂—; asingle bond; —S(O)₂—; —C(O)—; or —CH(CH₃)—.

In one embodiment of the presently disclosed compounds, the compound hasstructural formula (II):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (III):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (IV):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (V):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (VI):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (VII):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (VIII):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (IX):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas the structural formula (X):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XI):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XII):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XIII):

in which the variables are defined as described above with reference tostructural formula (I).

In one embodiment of the presently disclosed compounds, the compound hasstructural formula (XIV):

in which the variables are defined as described above with reference tostructural formula (I). In certain embodiments, one R¹⁴ is substitutedon the furano carbon. In other embodiments, no R¹⁴ is substituted on thefurano carbon.

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XV):

in which the variables are defined as described above with reference tostructural formula (I). In certain embodiments, one R¹⁴ is substitutedon the furano carbon. In other embodiments, no R¹⁴ is substituted on thefurano carbon.

In one embodiment of the presently disclosed compounds, the compound hasstructural formula (XVI):

in which the variables are defined as described above with reference tostructural formula (I). In certain embodiments, one R¹⁴ is substitutedon the thieno carbon. In other embodiments, no R¹⁴ is substituted on thethieno carbon.

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XVII):

in which the variables are defined as described above with reference tostructural formula (I). In certain embodiments, one R¹⁴ is substitutedon the thieno carbon. In other embodiments, no R¹⁴ is substituted on thethieno carbon.

The presently disclosed compounds include S-oxidized forms of thebenzothiophene compounds described (e.g., with reference to structuralformulae (XVI) and (XVII). S-oxides include, for example, sulfoxides(—SO—) and sulfones (—SO₂—). Such compounds may be oxidized chemicallyor upon administration to e.g. a human subject, may be oxidizedbiologically. Chemically oxidized compounds may also be biologicallyreduced to the benzothiophene form.

In one embodiment of the presently disclosed compounds, the compound hasstructural formula (XVIII):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XIX):

in which the variables are defined as described above with reference tostructural formula (I).

In certain embodiments of the compounds disclosed with respect tostructural formulae (I)-(XIX), n is 1 or 2. For example, in oneembodiment, n is 2. In another embodiment, n is 1.

In one embodiment of the presently disclosed compounds, the compound hasthe structural formula (XX):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XXI):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XXII):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XXIII):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XXIV):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XXV):

in which the variables are defined as described above with reference tostructural formula (I).

In one embodiment of the presently disclosed compounds, the compound hasstructural formula (XXVI):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XXVII):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XXVIII):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XXIX):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XXX):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XXXI):

in which the variables are defined as described above with reference tostructural formula (I).

In one embodiment of the presently disclosed compounds, the compound hasstructural formula (XXXII):

in which the variables are defined as described above with reference tostructural formula (I). In certain embodiments, one R¹⁴ is substitutedon the furano carbon. In other embodiments, no R¹⁴ is substituted on thefurano carbon.

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XXXIII):

in which the variables are defined as described above with reference tostructural formula (I). In certain embodiments, one R¹⁴ is substitutedon the furano carbon. In other embodiments, no R¹⁴ is substituted on thefurano carbon.

In one embodiment of the presently disclosed compounds, the compound hasstructural formula (XXXIV):

in which the variables are defined as described above with reference tostructural formula (I). In certain embodiments, one R¹⁴ is substitutedon the thieno carbon. In other embodiments, no R¹⁴ is substituted on thethieno carbon.

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XXXV):

in which the variables are defined as described above with reference tostructural formula (I). In certain embodiments, one R¹⁴ is substitutedon the thieno carbon. In other embodiments, no R¹⁴ is substituted on thethieno carbon.

In one embodiment of the presently disclosed compounds, the compound hasstructural formula (XXXVI):

in which the variables are defined as described above with reference tostructural formula (I).

In another embodiment of the presently disclosed compounds, the compoundhas structural formula (XXXVII):

in which the variables are defined as described above with reference tostructural formula (I).

In certain embodiments of the presently disclosed compounds of any ofstructural formulae (I)-(XXXVII), R¹ is —H. In other embodiments, R¹ is(C₁-C₄ alkyl), for example methyl, ethyl, n-propyl or isopropyl.

In certain embodiments of the presently disclosed compounds of anystructural formulae (I)-(XXXVII), R² is -Hca. In certain embodiments, R²is an optionally-substituted monocyclic heterocycloalkyl. In anotherembodiment, R² is not an oxo-substituted heterocycloalkyl.

In certain particular compounds disclosed herein having any ofstructural formulae (I)-(XXXVII), R² is -(optionally-substitutedazetidinyl), -(optionally-substituted pyrrolidinyl),-(optionally-substituted piperidinyl), or -(optionally-substitutedazepanyl). For example, R² can be -(optionally substituted piperidinyl)or -(optionally substituted pyrrolidinyl). In one embodiment, R² is-(optionally substituted piperidinyl). In another embodiment, R² is-(optionally substituted pyrrolidinyl).

In particular embodiments of the presently disclosed compounds of any ofstructural formulae (I)-(XXXVII), R² is -(optionally-substitutedazetidin-3-yl), -(optionally substituted piperidin-4-yl), -(optionallysubstituted pyrrolidin-3-yl) or -(optionally-substituted azepan-4-yl).For example, in one embodiment, R² is -(optionally substitutedpiperidin-4-yl). In another embodiment, R² is -(optionally substitutedpyrrolidin-3-yl).

In certain embodiments of the presently disclosed compounds of any ofstructural formulae (I)-(XXXVII), the azetidinyl, pyrrolidinyl,piperidinyl and azepanyl R² moieties described above are substituted attheir 1-positions. For example, in one embodiment, R² is substituted atits 1-position with —(C₀-C₃ alkyl)-Ar or —(C₀-C₃ alkyl)-Het, for example-(unsubstituted C₀-C₃ alkyl)-Ar or -(unsubstituted C₀-C₃ alkyl)-Het. Forexample, in one particular embodiment, the azetidinyl, pyrrolidinyl,piperidinyl or azepanyl R² moiety is substituted at its 1-position withan optionally substituted benzyl or an optionally substituted phenyl. Inanother embodiment, the azetidinyl, pyrrolidinyl, piperidinyl orazepanyl R² moiety is substituted at its 1-position with a benzylsubstituted with an electron withdrawing group; or with apyridinylmethyl optionally substituted with an electron withdrawinggroup. For example, the benzyl or pyridinylmethyl can be substitutedwith an electron withdrawing group selected from the group consisting ofhalo, cyano, —(C₁-C₄ fluoroalkyl), —O—(C₁-C₄ fluoroalkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl),—S(O)₂O—(C₀-C₄ alkyl), NO₂ and —C(O)—Hca in which the Hca includes anitrogen atom to which the —C(O)— is bound, in which no alkyl,fluoroalkyl or heterocycloalkyl is substituted with an aryl, heteroaryl,cycloalkyl or heterocycloalkyl-containing group. In other embodiments,the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R² moiety issubstituted at its 1-position with an unsubstituted benzyl or anunsubstituted phenyl.

In other embodiments of the compounds disclosed herein having any ofstructural formulae (I)-(XXXVII), the azetidinyl, pyrrolidinyl,piperidinyl or azepanyl R² moiety is substituted at its 1-position withan optionally substituted pyridinylmethyl, an optionally substitutedfuranylmethyl or an optionally substituted thienylmethyl. For example,the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R² moiety can besubstituted with an unsubstituted pyridinylmethyl, an unsubstitutedfuranylmethyl, or an unsubstituted thienylmethyl.

In other embodiments of the presently disclosed compounds of any ofstructural formulae (I)-(XXXVII), the azetidinyl, pyrrolidinyl,piperidinyl or azepanyl R² moiety is substituted at its 1-position with—C(O)—O(C₀-C₆ alkyl), —C(O)—Het, —C(O)—Ar, —S(O)₂-Het, —S(O)₂—Ar or—S(O)₂—O(C₀-C₆ alkyl).

In certain embodiments of the compounds of any of structural formulae(I)-(XXXVII), R² is -Cak-N(R⁹)-G-R²², as described above. For example,in one embodiment of the disclosed compounds, R² has the structure

in which b is 0, 1, 2, 3 or 4, and each R²¹ is independently selectedfrom —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷,—(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,—(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R²¹ on thesame carbon optionally combine to form oxo. In certain embodiments ofthe presently disclosed compounds, each R²¹ is independently selectedfrom —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (e.g., trifluoromethyl), —(C₀-C₆alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN andtwo R²¹ on the same carbon optionally combine to form oxo, in which eachR⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkylor haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in one embodiment, eachR²¹ is —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN and two R²¹ on the same carbonoptionally combine to form oxo, in which each R⁷, R⁸ and R¹⁰ isindependently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl),—(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. In certain embodiments, b is 1 or 2.In other embodiments, b is 0. In certain embodiments, R⁹ is H. Incertain embodiments, G is a single bond.

In one embodiment of compounds of any of structural formulae(I)-(XXXVII), R² has the structure

In certain embodiments of the compounds of any of structural formulae(I)-(XXXVII), R² is —(C₂-C₈ alkyl)-N(R⁹)—R²⁴ in which one or two carbonsof the (C₂-C₈ alkyl) are optionally replaced by —O— or —N(R⁹)— and R²⁴is —R²³, -GR²³, or —C(O)O—(C₁-C₆ alkyl). In certain embodiments, the(C₂-C₈ alkyl) is unsubstituted and no carbon is replaced by —O— or—N(R⁹)—. For example, in one embodiment, R² is —CH₂—CH₂—CH₂—N(R⁹)—R²⁴ or—CH₂—CH₂—CH₂—CH₂—N(R⁹)—R²⁴. In other embodiments, the (C₂-C₈ alkyl) issubstituted and/or one or two carbons are replaced by —O— or —N(R⁹)—.For example, in one embodiment, R² is —CH₂—CH₂—O—CH₂—CH₂—N(R⁹)—R²⁴;—CH₂—CH(CH₃)—N(R⁹)—R²⁴; or —CH₂—CH₂—O—CH₂—C(O)—N(R⁹)—R²⁴. In certainembodiments, R⁹ is H. In certain embodiments, R²⁴ is Ar or Het. Incertain embodiments, the (C₂-C₈ alkyl) is a (C₂-C₅ alkyl).

In the compounds of any of structural formulae (I)-(XXXVII), w is 0, 1,2 or 3. For example, in one embodiment, w is 0, 1 or 2. In anotherembodiment, w is 0. In other embodiments, w is at least 1, and at leastone R³ is selected from the group consisting of halo, cyano, —(C₁-C₄fluoroalkyl), —O—(C₁-C₄ fluoroalkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), —S(O)₂O—(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca includes a nitrogen atom to which the —C(O)—is bound, in which no alkyl, fluoroalkyl or heterocycloalkyl issubstituted with an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In certain embodiments, an R³ issubstituted on the “B” ring system at a benzo or pyrido ring positionmeta to the alicyclic ethereal oxygen.

In certain embodiments of the compounds of any of structural formulae(I)-(XXXVII), each R³ is independently selected from —(C₁-C₆ alkyl),—(C₁-C₆ haloalkyl) (e.g., trifluoromethyl), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl),—(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl), and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in one embodiment, eachR³ is —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl),—(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group.

In certain embodiments of the compounds of any of structural formulae(I)-(XXXVII), w is at least one, and at least one R³ is —NR⁸R⁹. Forexample, in one embodiment, w is 1. In certain such embodiments, R³ issubstituted on the “B” ring system at a benzo or pyrido ring positionmeta to the alicyclic ethereal oxygen.

In other embodiments of the compounds of any of structural formulae(I)-(XXXVII), w is at least one, and at least one R³ is —(C₀-C₃alkyl)-Y¹—(C₁-C₃ alkyl)-Y²—(C₀-C₃ alkyl), in which each of Y¹ and Y² isindependently L, —O—, —S— or —NR⁹—. For example, in one embodiment, wis 1. In certain such embodiments, R³ is substituted on the “B” ringsystem at a benzo or pyrido ring position meta to the alicyclic etherealoxygen. In one particular embodiment, R³ is —CH₂—N(CH₃)—CH₂—C(O)—OCH₃.

In the presently disclosed compounds of any of structural formulae(I)-(XXXVII), the number of substituents on the azacycloalkyl ring, x,is 0, 1, 2, 3 or 4. In one embodiment, x is 0, 1, 2 or 3. For example, xcan be 0, or can be 1 or 2.

In certain embodiments of the presently disclosed compounds of any ofstructural formula (I)-(XXXVII), two R⁴s combine to form an oxo. The oxocan be bound, for example, at the position alpha to the nitrogen of theazacycloalkyl ring. In other embodiments, no two R⁴s combine to form anoxo.

In certain embodiments of the presently disclosed compounds of any ofstructural formulae (I)-(XXXVII), when x is 4, not all four R⁴ moietiesare (C₁-C₆ alkyl).

In certain embodiments of the presently disclosed compounds of any ofstructural formulae (I)-(XXXVII), each R⁴ is independently selected from—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (e.g., trifluoromethyl), —(C₀-C₆alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, inwhich each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), andin which no alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Forexample, in one embodiment, each R⁴ is —(C₁-C₃ alkyl), —(C₁-C₃haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group.

In certain embodiments, the presently disclosed compounds have thestructural formula (XXXVIII):

in which Q and G are each independently a bond, —CH₂—, —C(H)(R¹⁶)—,—C(R¹⁶)₂— or —S(O)₂—; v is 0, 1, 2, 3 or 4; each R¹⁵ is independentlyselected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar,—(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, andtwo R¹⁵ on the same carbon optionally combine to form oxo; R¹⁷ is Het orAr, and all other variables are defined as described above withreference to structural formula (I)-(XXXVII). In one embodiment, Q is asingle bond. In another embodiment, Q is —CH₂—. In other embodiments, Qis —C(O)— or —S(O)₂—. In certain embodiments, G is —CH₂—. In otherembodiments, G is —C(O)— or —S(O)₂—. In other embodiments, G is—CH(CH₃)—. For example, in one embodiment, Q is a single bond and G is—CH₂— or —C(O)—. As described above, in certain embodiments, the ringsystem denoted by “A” is aryl or heteroaryl. In one embodiment, the ringsystem denoted by “A” is substituted with one or moreelectron-withdrawing groups. In another embodiment, R¹⁷ is substitutedwith one or more electron-withdrawing groups. In certain embodiments,the ring system denoted by “A”, R¹⁷ or both are not substituted with anaryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group.

In the presently disclosed compounds of structural formula (XXXVIII), vis 0, 1, 2, 3 or 4. In one embodiment, v is 0, 1, 2 or 3. For example, vcan be 0, or can be 1 or 2.

In certain embodiments of the presently disclosed compounds ofstructural formula (XXXVIII), two R¹⁵s combine to form an oxo. The oxocan be bound, for example, at the position alpha to the nitrogen of theazacycloalkyl ring. In other embodiments, no two R¹⁵s combine to form anoxo.

In certain embodiments of the presently disclosed compounds ofstructural formula (XXXVIII), when v is 4, not all four R¹⁵ moieties are(C₁-C₆ alkyl).

In certain embodiments of the presently disclosed compounds ofstructural formula (XXXVIII), each R¹⁵ is independently selected from—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (e.g., trifluoromethyl), —(C₀-C₆alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN andtwo R¹⁵ on the same carbon optionally combine to form oxo, in which eachR⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkylor haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in one embodiment, eachR¹⁵ is —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN and two R¹⁵ on the same carbonoptionally combine to form oxo, in which each R⁷, R⁸ and R¹⁰ isindependently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl),—(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. In some embodiments, one R¹⁵ is—C(O)NR⁹R⁷, which can be bound, for example, at a position alpha to thepiperidine nitrogen, or at the position linked to the —N(R¹)—.

In certain embodiments of the presently disclosed compounds ofstructural formula (XXXVIII), R¹⁷ is an unsubstituted aryl orheteroaryl. In other embodiments, the R¹⁷ Ar or Het is substituted with1, 2 or 3 substituents independently selected from —(C₁-C₆ alkyl),—(C₁-C₆ haloalkyl) (e.g., trifluoromethyl), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl),—(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in one embodiment, theR¹⁷ Ar or Het is substituted with 1, 2 or 3 substituents independentlyselected from —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷,—(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰,—(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸and R¹⁰ is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkylor haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. In certain embodiments, R¹⁷ issubstituted with 1, 2 or 3 substituents selected from halo, cyano,—(C₁-C₄ haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄alkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄alkyl)(C₀-C₄ alkyl), NO₂ and —C(O)—Hca. R¹⁷ can be substituted with, forexample, one such substituent, or two such substituents.

In certain embodiments, the presently disclosed compounds have thestructural formula (XXXIX):

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., trifluoromethyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in whichno heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R²⁹is —H, —(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl)is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca, and all other variables areas described above with respect to structural formulae (I) and(XXXVIII).

In certain embodiments, the presently disclosed compounds have thestructural formula (XL):

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., trifluoromethyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in whichno heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R²⁹is —H, —(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl)is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca, and all other variables areas described above with respect to structural formulae (I) and(XXXVIII).

In certain embodiments, the presently disclosed compounds have thestructural formula (XLI):

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., trifluoromethyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in whichno heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R²⁹is —H, —(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl)is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca, and all other variables areas described above with respect to structural formulae (I) and(XXXVIII).

In certain embodiments, the presently disclosed compounds have thestructural formula (XLII):

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., trifluoromethyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in whichno heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R²⁹is —H, —(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl)is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca, and all other variables areas described above with respect to structural formulae (I) and(XXXVIII).

In certain embodiments, the presently disclosed compounds have thestructural formula (XLIII):

in which all variables are as described above with respect to structuralformulae (I) and (XXXVIII).

In certain embodiments, the presently disclosed compounds have thestructural formula (XLIV):

in which R²⁵ is selected from halo, cyano, —(C₁-C₄ haloalkyl), —O—(C₁-C₄haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄ alkyl),—C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl or haloalkyl is substitutedby an aryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group;and all other variables are as described above with respect tostructural formulae (I) and (XXXVIII). R²⁵ can be, for example, —Cl, —F,cyano, —C(O)CH₃, —C(O)OH, —C(O)NH₂, trifluoromethyl, difluoromethyl,difluoromethoxy or trifluoromethoxy.

In certain embodiments, the presently disclosed compounds have thestructural formula (XLV):

in which G is —C(O)— or —S(O)₂— and all other variables are as describedabove with respect to structural formulae (I) and (XXXVIII).

In certain embodiments, the presently disclosed compounds have thestructural formula (XLVI):

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., trifluoromethyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in whichno heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R²⁹is —H, —(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl)is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca, and all other variables areas described above with respect to structural formulae (I) and(XXXVIII). In some embodiments, the compounds of structural formula(XLVI) are present as racemic mixtures or scalemic mixtures. In otherembodiments, the compounds of structural formula (XLVI) are present inan enantiomerically-enriched form, for example as a substantially purestereoisomer.

In certain embodiments, the presently disclosed compounds have thestructural formula (XLVII):

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., trifluoromethyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in whichno heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R²⁹is —H, —(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl)is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca, and all other variables areas described above with respect to structural formulae (I) and(XXXVIII). In some embodiments, the compounds of structural formula(XLVII) are present as racemic mixtures or scalemic mixtures. In otherembodiments, the compounds of structural formula (XLVII) are present inan enantiomerically-enriched form, for example as a substantially purestereoisomer.

In certain embodiments, the presently disclosed compounds have thestructural formula (XLVIII):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII).

In certain embodiments, the presently disclosed compounds have thestructural formula (XLIX):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII).

In certain embodiments, the presently disclosed compounds have thestructural formula (L):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII).

In certain embodiments, the presently disclosed compounds have thestructural formula (LI):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII).

In certain embodiments, the presently disclosed compounds have thestructural formula (LII):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII).

In certain embodiments, the presently disclosed compounds have thestructural formula (LIII):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII).

In certain embodiments, the presently disclosed compounds have thestructural formula (LIV):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII).

In certain embodiments, the presently disclosed compounds have thestructural formula (LV):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII).

In certain embodiments, the presently disclosed compounds have thestructural formula (LVI):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII).

In certain embodiments, the presently disclosed compounds have thestructural formula (LVII):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII).

In certain embodiments, the presently disclosed compounds have thestructural formula (LVIII):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII).

In certain embodiments, the presently disclosed compounds have thestructural formula (LIX):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII).

In certain embodiments, the presently disclosed compounds have thestructural formula (LX):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII). In certain embodiments, one R¹⁴ is substituted on thefurano carbon. R¹⁴ can be, for example, as described above withreference to structural formula (I). For example, in one embodiment R¹⁴is halo (e.g., —Cl or —F), cyano unsubstituted —(C₁-C₄ alkyl) (e.g.,methyl or ethyl), unsubstituted —(C₁-C₄ haloakyl) (e.g.,trifluoromethyl). In other embodiments, no R¹⁴ is substituted on thefurano carbon.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXI):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII). In certain embodiments, one R¹⁴ is substituted on thefurano carbon. R¹⁴ can be, for example, as described above withreference to structural formula (I). For example, in one embodiment R¹⁴is halo (e.g., —Cl or —F), cyano unsubstituted —(C₁-C₄ alkyl) (e.g.,methyl or ethyl), unsubstituted —(C₁-C₄ haloakyl) (e.g.,trifluoromethyl). In other embodiments, no R¹⁴ is substituted on thefurano carbon.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXII):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII). In certain embodiments, one R¹⁴ is substituted on thethieno carbon. R¹⁴ can be, for example, as described above withreference to structural formula (I). For example, in one embodiment R¹⁴is halo (e.g., —Cl or —F), cyano unsubstituted —(C₁-C₄ alkyl) (e.g.,methyl or ethyl), unsubstituted —(C₁-C₄ haloakyl) (e.g.,trifluoromethyl). In other embodiments, no R¹⁴ is substituted on thethieno carbon.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXIII):

in which G, v, R¹⁵ and R¹⁷ are defined as described above with referenceto structural formula (XXXVIII), and all other variables are defined asdescribed above with reference to structural formulae (I) and (XXXVIII).R⁵, v, R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, forexample, as described with respect to any of structural formulae(XXXIX)-(XLVII). In certain embodiments, one R¹⁴ is substituted on thethieno carbon. R¹⁴ can be, for example, as described above withreference to structural formula (I). For example, in one embodiment R¹⁴is halo (e.g., —Cl or —F), cyano unsubstituted —(C₁-C₄ alkyl) (e.g.,methyl or ethyl), unsubstituted —(C₁-C₄ haloakyl) (e.g.,trifluoromethyl). In other embodiments, no R¹⁴ is substituted on thethieno carbon.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXIV):

in which Q, G, v, R¹⁵ and R¹⁷ are defined as described above withreference to structural formula (XXXVIII), and all other variables aredefined as described above with reference to structural formula (I). R⁵,R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, for example,as described with respect to any of structural formulae (XXXIX)-(XLVII).

In certain embodiments, the presently disclosed compounds have thestructural formula (LXV):

in which Q, G, v, R¹⁵ and R¹⁷ are defined as described above withreference to structural formula (XXXVIII), and all other variables aredefined as described above with reference to structural formula (I). R⁵,R¹⁵, R¹⁷, Q, G and the ring denoted by “A” can be defined, for example,as described with respect to any of structural formulae (XXXIX)-(XLVII).

In certain embodiments of compounds having structural formulae(XXXVIII)-(LXV), the

moiety has the structure

in which G is —CH₂—, —CH(CH₃)—, —C(O)— or —S(O)₂—. For example, in oneembodiment, G is —CH₂—. In another embodiment, G is —C(O)— or —S(O)₂—.

In other embodiments of compounds having structural formulae(XXXVIII)-(LXV), the

moiety has the structure

in which G is —CH₂—, —C(O)— or —S(O)₂—. In such embodiments, thecompounds of structural formula (XLVII) can be present as racemicmixtures or scalemic mixtures, or in an enantiomerically-enriched form,for example as a substantially pure stereoisomer.

In other embodiments of compounds having structural formulae(XXXVIII)-(LXV), the

moiety has the structure

in which G is —CH₂—, —C(O)— or —S(O)₂—.

In certain embodiments of compounds having structural formulae(XXXVIII)-(LXV), the R¹⁷ moiety has the structure

in which R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl)(e.g., trifluoromethyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in whichno heterocycloalkyl, alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group, and R²⁹is —H, —(C₁-C₄ alkyl) or —CO—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl)is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca.

In certain embodiments described above, each R²⁷ is selected from—(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN and two R²¹ on the same carbonoptionally combine to form oxo, in which each R⁷, R⁸ and R¹⁰ isindependently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl),—(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group, and each R²⁹ is H, methyl or ethyl,or R²⁷ and R²⁹ together with the nitrogen to which they are bound formHca.

In certain embodiments of compounds having structural formulae(XXXVIII)-(LXV), the

moiety is p-(trifluoromethyl)phenyl.

In one embodiment, the presently disclosed compounds have the structuralformula (LXVI):

in which G, R³ and R¹⁷ are as described above with respect to structuralformula (XXXVIII); R¹⁸ is H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (e.g.,trifluoromethyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), inwhich no alkyl or haloalkyl is substituted with an aryl-, heteroaryl-,cycloalkyl- or heterocycloalkyl-containing group and R¹⁹ is —H, —(C₁-C₄alkyl) or —CO—O—(C₁-C₄ alkyl) in which no alkyl is substituted by anaryl, heteroaryl, cycloalkyl or heterocycloalkyl-containing group, orR¹⁸ and R¹⁹ together with the nitrogen to which they are bound form Hca;and R²° is Ar or Het. In certain embodiments, R¹⁸ is H or (C₁-C₄ alkyl),and R¹⁹ is —H. In certain embodiments, one R¹⁴ is substituted on thefurano carbon. R¹⁴ can be, for example, as described above withreference to structural formula (I). For example, in one embodiment R¹⁴is halo (e.g., —Cl or —F), cyano unsubstituted —(C₁-C₄ alkyl) (e.g.,methyl or ethyl), unsubstituted —(C₁-C₄ haloakyl) (e.g.,trifluoromethyl). In other embodiments, no R¹⁴ is substituted on thefurano carbon.

In certain embodiments of compounds of structural formula (LXVI), w is1, and R³ is —NR⁸R⁹. In certain such embodiments, R³ is substituted at abenzo or pyrido ring position meta to the alicyclic ethereal oxygen.

In other embodiments of compounds of structural formula (LXVI), w is 1,and R³ is —(C₀-C₃ alkyl)-Y¹—(C₁-C₃ alkyl)-Y²—(C₀-C₃ alkyl), in whicheach of Y¹ and Y² is independently L, —O—, —S— or —NR⁹—. In certain suchembodiments, R³ is substituted at a benzo or pyrido ring position metato the alicyclic ethereal oxygen.

In another embodiment, the presently disclosed compounds have thestructural formula (LXVII):

in which R³ and R¹⁴ are defined as described above with reference tostructural formulae (I) and (XXXVIII); G and R¹⁷ are defined asdescribed above with reference to structural formula (XXXVIII); and R¹⁸and R¹⁹ are defined as described above with reference to structuralformula (LXVI).

In another embodiment, the presently disclosed compounds have thestructural formula (LXVIII):

in which R³ and R¹⁴ are defined as described above with reference tostructural formulae (I) and (XXXVIII); G and R¹⁷ are defined asdescribed above with reference to structural formula (XXXVIII); and R¹⁸and R¹⁹ are defined as described above with reference to structuralformula (LXVI).

In another embodiment, the presently disclosed compounds have thestructural formula (LXIX):

in which R³ and R¹⁴ are defined as described above with reference tostructural formulae (I) and (XXXVIII); G and R¹⁷ are defined asdescribed above with reference to structural formula (XXXVIII); and R¹⁸and R¹⁹ are defined as described above with reference to structuralformula (LXVI).

In another embodiment, the presently disclosed compounds have thestructural formula (LXX):

in which Q, R³, R⁵ and R¹⁴ are defined as described above with referenceto structural formulae (I) and (XXXVIII); and R¹⁸ and R¹⁹ are defined asdescribed above with reference to structural formula (LXVI).

In another embodiment, the presently disclosed compounds have thestructural formula (LXXI):

in which R³, R⁵ and R¹⁴ are defined as described above with reference tostructural formulae (I) and (XXXVIII); and R¹⁸ and R¹⁹ are defined asdescribed above with reference to structural formula (LXVI).

In another embodiment, the presently disclosed compounds have thestructural formula (LXXII):

in which Q, R³, R⁵ and R¹⁴ are defined as described above with referenceto structural formulae (I) and (XXXVIII); and R¹⁸ and R¹⁹ are defined asdescribed above with reference to structural formula (LXVI).

In another embodiment, the presently disclosed compounds have thestructural formula (LXXIII):

in which R³, R⁵ and R¹⁴ are defined as described above with reference tostructural formulae (I) and (XXXVIII); and R¹⁸ and R¹⁹ are defined asdescribed above with reference to structural formula (LXVI).

In another embodiment, the presently disclosed compounds have thestructural formula (LXXIV):

in which R³, R⁵ and R¹⁴ are defined as described above with reference tostructural formulae (I) and (XXXVIII); and R¹⁸ and R¹⁹ are defined asdescribed above with reference to structural formula (LXVI).

In one embodiment, the presently disclosed compounds have the structuralformula (LXXV):

in which one J is N and the other is CH; Q is —CH₂— or a single bond; Gis CH₂ or C(O); R³ is as described above with respect to structuralformulae (I) and (XXXVIII) (e.g., absent or halo); and R¹¹, R¹² and R¹³are independently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXVI):

in which one J is N and the other is CH; Q is —CH₂— or a single bond; Gis CH₂ or C(O); R³ is as described above with respect to structuralformulae (I) and (XXXVIII) (e.g., absent or halo); and R¹¹, R¹² and R¹³are independently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXVII):

in which one J is N, and the other is CH; Q is —CH₂— or a single bond; Gis CH₂ or C(O); R³ is as described above with respect to structuralformulae (I) and (XXXVIII) (e.g., absent or halo); and R¹² and R¹³ areindependently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXVIII):

in which one J is N, and the other three are CH; Q is —CH₂— or a singlebond; G G is CH₂ or C(O); R³ is as described above with respect tostructural formulae (I) and (XXXVIII) (e.g., absent or halo); and R¹²and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXIX):

in which one J is N and the other is CH; Q is —CH₂— or a single bond Gis CH₂ or C(O); R³ is as described above with respect to structuralformulae (I) and (XXXVIII) (e.g., absent or halo); and R¹¹, R¹² and R¹³are independently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXX):

in which one J is N, and the other three are CH; Q is —CH₂— or a singlebond; G is CH₂ or C(O); R³ is as described above with respect tostructural formulae (I) and (XXXVIII) (e.g., absent or halo); and R¹¹,R¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXXI):

in which one J is N, and the other is CH; Q is —CH₂— or a single bond; Gis CH₂ or C(O); R³ is as described above with respect to structuralformulae (I) and (XXXVIII) (e.g., absent or halo); and R¹² and R¹³ areindependently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXXII):

in which one J is N, and the other three are CH; Q is —CH₂— or a singlebond; G is CH₂ or C(O); R³ is as described above with respect tostructural formulae (I) and (XXXVIII) (e.g., absent or halo); and R¹²and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXXIII):

in which Q is —CH₂— or a single bond; G is CH₂ or C(O); R³ is asdescribed above with respect to structural formulae (I) and (XXXVIII)(e.g., absent or halo); R¹⁴ is as described above with respect tostructural formulae (I) and (LX) (e.g., absent, methyl or halo); andR¹¹, R¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXXIV):

in which Q is —CH₂— or a single bond; G is CH₂ or C(O); R³ is asdescribed above with respect to structural formulae (I) and (XXXVIII)(e.g., absent or halo); R¹⁴ is as described above with respect tostructural formulae (I) and (LXI) (e.g., absent, methyl or halo); andR¹¹, R¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXXV):

in which Q is —CH₂— or a single bond; G is CH₂ or C(O); R³ is asdescribed above with respect to structural formulae (I) and (XXXVIII)(e.g., absent or halo); R¹⁴ is as described above with respect tostructural formulae (I) and (LX) (e.g., absent, methyl or halo); and R¹²and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXXVI):

in which Q is —CH₂— or a single bond; G is CH₂ or C(O); R³ is asdescribed above with respect to structural formulae (I) and (XXXVIII)(e.g., absent or halo); R¹⁴ is as described above with respect tostructural formulae (I) and (LXI) (e.g., absent, methyl or halo); andR¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXXVII):

in which Q is —CH₂— or a single bond; G is CH₂ or C(O); R³ is asdescribed above with respect to structural formulae (I) and (XXXVIII)(e.g., absent or halo); R¹⁴ is as described above with respect tostructural formulae (I) and (LXII) (e.g., absent, methyl or halo); andR¹¹, R¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXXVIII):

in which Q is —CH₂— or a single bond; G is CH₂ or C(O); R³ is asdescribed above with respect to structural formulae (I) and (XXXVIII)(e.g., absent or halo); R¹⁴ is as described above with respect tostructural formulae (I) and (LXIII) (e.g., absent, methyl or halo); andR¹¹, R¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXXIX):

in which Q is —CH₂— or a single bond; G is CH₂ or C(O); R³ is asdescribed above with respect to structural formulae (I) and (XXXVIII)(e.g., absent or halo); R¹⁴ is as described above with respect tostructural formulae (I) and (LXII) (e.g., absent, methyl or halo); andR¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (XC):

in which Q is —CH₂— or a single bond; G is CH₂ or CO; G is CH₂ or C(O);R³ is as described above with respect to structural formulae (I) and(XXXVIII) (e.g., absent or halo); R¹⁴ is as described above with respectto structural formulae (I) and (LXIII) (e.g., absent, methyl or halo);and R¹² and R¹³ are independently selected from H, halo, cyano, —(C₁-C₄haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl),—C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄alkyl), NO₂ and —C(O)—Hca in which the Hca contains a ring nitrogen atomthrough which it is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (XCI):

in which Q is —CH₂— or a single bond; G is CH₂ or C(O); R³ is asdescribed above with respect to structural formulae (I) and (XXXVIII)(e.g., absent or halo); R¹⁴ is as described above with respect tostructural formula (I) (e.g., absent, methyl or halo); and R¹¹, R¹² andR¹³ are independently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (XCII):

in which Q is —CH₂— or a single bond; G is CH₂ or C(O); R³ is asdescribed above with respect to structural formulae (I) and (XXXVIII)(e.g., absent or halo); R¹⁴ is as described above with respect tostructural formula (I) (e.g., absent, methyl or halo); and R¹¹, R¹² andR¹³ are independently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (XCIII):

in which Q is —CH₂— or a single bond; G is CH₂ or C(O); R³ is asdescribed above with respect to structural formulae (I) and (XXXVIII)(e.g., absent or halo); R¹⁴ is as described above with respect tostructural formula (I) (e.g., absent, methyl or halo); and R¹² and R¹³are independently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H.

In certain embodiments, the presently disclosed compounds have thestructural formula (XCIV):

in which Q is —CH₂— or a single bond; G is CH₂ or C(O); R³ is asdescribed above with respect to structural formulae (I) and (XXXVIII)(e.g., absent or halo); R¹⁴ is as described above with respect tostructural formula (I) (e.g., absent, methyl or halo); and R¹² and R¹³are independently selected from H, halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, in which no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In one particular such embodiment, atleast one of R¹¹, R¹² and R¹³ is not H.

Examples of compounds according to structural formula (I) include thoselisted in Table 1. These compounds can be made according to the generalschemes described below, for example using a procedure analogous tothose described below in the Examples.

TABLE 1 No. Name Structure  1 5-(1-(4-cyanophenyl) piperidin-4-yloxy)-N-(1-(pyridin-4- ylmethyl)piperidin-4- yl)picolinamide

 2 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(1-(4-cyanophenyl) piperidin-4-yloxy)picolinamide

 3 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide

 4 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide

 5 N-(1-(pyridin-3- ylmethyl)piperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide

 6 N-(1-(pyridin-3- ylmethyl)piperidin- 4-yl)-5-(1-(4-cyanophenyl)piperidin-4- yloxy)picolinamide

 7 methyl 4-((4-(5-(1-(4- cyanophenyl)piperidin-4- yloxy)picolinamido)piperidin-1- yl)methyl)benzoate

 8 methyl 4-((4-(5-(1-(4- (trifluoromethyl)phenyl) piperidin-4-yloxy)picolinamido) piperidin-1- yl)methyl)benzoate

 9 tert-butyl 4-(6-(1-(4- (trifluoromethyl)phenyl) piperidin-4-yloxy)nicotinamido) piperidine-1- carboxylate

 10 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)nicotinamide

 11 N-(1-(4-fluorobenzyl) piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)nicotinamide

 12 tert-butyl 4-(4-(1-(4- (trifluoromethyl)phenyl) piperidin-4-yloxy)picolinamido) piperidine-1- carboxylate

 13 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-4-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)picolinamide

 14 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)nicotinamide

 15 tert-butyl 4-(2-(1-(4- (trifluoromethyl) phenyl)piperidin- 4-yloxy)isonicotinamido) piperidine- 1-carboxylate

 16 N-(1-(4-fluorobenzyl) piperidin-4- yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)nicotinamide

 17 N-(1-(4-cyanobenzyl) piperidin-4- yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)nicotinamide

 18 N-(1-(pyridin-3- ylmethyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)nicotinamide

 19 N-(piperidin-4-yl)-2-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)isonicotinamide

 20 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-2-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)isonicotinamide

 21 N-(1-(4-cyanobenzyl) piperidin-4- yl)-2-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)isonicotinamide

 22 N-(1-(4-fluorobenzyl) piperidin-4- yl)-2-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)isonicotinamide

 23 (R)-tert-butyl 3-(5-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)picolinamido) pyrrolidine- 1-carboxylate

 24 (R)-N-(pyrrolidin-3- yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide

 25 (R)-N-(1-(pyridin-4- ylmethyl)pyrrolidin- 3-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)picolinamide

 26 (S)-tert-butyl 3-(5-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)picolinamido) pyrrolidine- 1-carboxylate

 27 (S)-N-(pyrrolidin- 3-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide

 28 N-(1-(4-cyanobenzyl) piperidin-4- yl)-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide

 29 N-(1-(4-fluorobenzyl) piperidin-4- yl)-4-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide

 30 (S)-N-(1-(pyridin-4- ylmethyl)pyrrolidin- 3-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)picolinamide

 31 (S)-N-(1-(4- cyanobenzyl)pyrrolidin- 3-yl)-5-(1- (4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)picolinamide

 32 (S)-N-(1-(4- fluorobenzyl)pyrrolidin- 3-yl)-5-(1- (4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)picolinamide

 33 (R)-N-(1-(4- cyanobenzyl)pyrrolidin- 3-yl)-5-(1- (4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)picolinamide

 34 (R)-N-(1-(4- fluorobenzyl)pyrrolidin- 3-yl)-5-(1- (4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)picolinamide

 35 N-(1-(4-cyanobenzyl) piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)nicotinamide

 36 N-(1-phenethylpiperidin- 4-yl)-5-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide

 37 N-(1-(naphthalen-2- ylmethyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)picolinamide

 38 N-(1-benzylpiperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide

 39 N-(1-(4- (dimethylamino) benzyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)picolinamide

 40 N-(1-(4- morpholinobenzyl) piperidin-4-yl)- 5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)picolinamide

 41 N-(1-(4-cyanobenzyl) azetidin-3- yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide

 42 N-(1-(pyridin-4- ylmethyl)azetidin- 3-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide

 43 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)picolinamide

 44 N-(1-(pyrimidin-5- ylmethyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)picolinamide

 45 methyl 4-((4-(6-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)nicotinamido) piperidin-1- yl)methyl)benzoate

 46 4-((4-(6-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)nicotinamido) piperidin-1- yl)methyl)benzoic acid

 47 5-(1-(4- (trifluoromethyl) phenyl)piperidin- 4-yloxy)-N-(1-((1-trityl-1H- imidazol-4-yl) methyl)piperidin-4- yl)picolinamide

 48 N-(1-((1H-imidazol-4- yl)methyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)picolinamide

 49 tert-butyl 3-(5-(1-(4- (trifluoromethyl) phenyl)piperidin- 4-yloxy)picolinamido) propylcarbamate

 50 N-(3-(pyridin-4- ylmethylamino) propyl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)picolinamide

 51 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)pyridine-3- sulfonamide

 52 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-6-(1-(4-cyanophenyl)piperidin-4- yloxy)pyridine-3- sulfonamide

 53 6-(1-(4-cyanobenzyl) piperidin-4- yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4- yl)pyridine-3- sulfonamide

 54 tert-butyl 4-(6-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)pyridine-3- sulfonamido)piperidine-1- carboxylate

 55 N-(piperidin-4-yl)-6-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)pyridine-3- sulfonamide

 56 N-(1-(4-cyanobenzyl) piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyridine- 3-sulfonamide

 57 N-(1-(3-cyanobenzyl) piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyridine- 3-sulfonamide

 58 N-(1-(4- (trifluoromethyl) benzyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)pyridine- 3-sulfonamide

 59 N-(1-(3- (trifluoromethyl) benzyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)pyridine- 3-sulfonamide

 60 N-(1-(4-fluorobenzoyl) piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)pyridine- 3-sulfonamide

 61 tert-butyl 4-(3- methyl-6-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)benzofuran-2- carboxamido)piperidine-1- carboxylate

 62 3-methyl-N- (piperidin-4-yl)-6-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 63 N-(1-(4-fluorobenzyl) piperidin-4- yl)-3-methyl-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 64 N-(1-(4-cyanobenzyl) piperidin-4- yl)-3-methyl-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 65 3-methyl-N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 66 N-(1-(3-cyanobenzyl) piperidin-4- yl)-3-methyl-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 67 N-(1-(2-cyanobenzyl) piperidin-4- yl)-3-methyl-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 68 3-methyl-N-(1-(pyridin-2- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 69 3-methyl-N-(1-(pyridin-3- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 70 N-(1-benzylpiperidin- 4-yl)-5-(1-(4- cyanobenzyl)piperidin-4-yloxy)benzofuran- 2-carboxamide

 71 N-(1-benzylpiperidin- 4-yl)-5-(1-(4- cyanophenyl)piperidin-4-yloxy)benzofuran- 2-carboxamide

 72 N-(1-benzylpiperidin- 4-yl)-5-(1-(4- chlorobenzyl)piperidin-4-yloxy)benzofuran- 2-carboxamide

 73 N-(1-benzylpiperidin- 4-yl)-5-(1-(3- (trifluoromethyl)benzyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 74 N-(1-benzylpiperidin- 4-yl)-5-(1- (3,4-difluorobenzyl) piperidin-4-yloxy)benzofuran- 2-carboxamide

 75 N-(1-benzylpiperidin- 4-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 76 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-5-(1-(4- trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 77 5-(1-(4-chlorobenzyl) piperidin-4- yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4- yl)benzofuran-2- carboxamide

 78 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethoxy) phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide

 79 5-(1-(4-cyanobenzyl) piperidin-4- yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4- yl)benzofuran-2- carboxamide

 80 N-(1-benzylpiperidin- 4-yl)-5-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide

 81 tert-butyl 4-(6-(1-(4- (trifluoromethoxy) phenyl)piperidin-4-yloxy)benzofuran-2- carboxamido)piperidine-1- carboxylate

 82 tert-butyl 4-(6-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)benzofuran-2- carboxamido)piperidine-1- carboxylate

 83 N-(piperidin-4-yl)-6-(1-(4- (trifluoromethoxy) phenyl)piperidin-4-yloxy)benzofuran-2- carboxamide

 84 N-(piperidin-4-yl)-6-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)benzofuran- 2-carboxamide

 85 tert-butyl 4-(5-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)benzofuran-2- carboxamido)piperidine-1- carboxylate

 86 N-(piperidin-4-yl)-5-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)benzofuran- 2-carboxamide

 87 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 88 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethoxy) phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide

 89 N-(1-(4-cyanobenzyl) piperidin-4- yl)-6-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide

 90 N-(1-(4-cyanobenzyl) piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 91 N-(1-(4-fluorobenzyl) piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 92 N-(1-(pyridin-2- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethoxy) phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide

 93 N-(1-(pyridin-2- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 94 N-(1-(4-fluorobenzyl) piperidin-4- yl)-6-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide

 95 N-(1-(pyridin-3- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethoxy) phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide

 96 N-(1-(pyridin-3- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 97 N-(1-(2-cyanobenzyl) piperidin-4- yl)-6-(1-(4- (trifluoromethoxy)phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide

 98 N-(1-(2-cyanobenzyl) piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

 99 N-(1-(4- (trifluoromethyl) benzyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

100 N-(1-(4- (trifluoromethyl) benzyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

101 N-(1-(pyridin-3- ylmethyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

102 tert-butyl 4-(N- methyl-5-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)benzofuran-2- carboxamido)piperidine-1- carboxylate

103 N-methyl-N- (piperidin-4-yl)-5-(1- (4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

104 N-methyl-N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

105 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide,formate salt

106 N-(1-(pyridin-3- ylsulfonyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

107 N-(1-(4-cyanobenzyl) piperidin-4- yl)-N-methyl-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

108 N-(1-(pyridin-3- ylsulfonyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethoxy) phenyl)piperidin- 4-yloxy)benzofuran-2- carboxamide

109 N-methyl-N-(1-(pyridin-3- ylmethyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

110 N-(1-(3-cyanobenzyl) piperidin-4- yl)-N-methyl-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

111 N-(1-(2-cyanobenzyl) piperidin-4- yl)-N-methyl-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

112 N-(1- isonicotinoylpiperidin- 4-yl)-6- (1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

113 tert-butyl 4-(5-(1-(4- cyanobenzyl)piperidin-4- yloxy)benzofuran-2-carboxamido)piperidine-1- carboxylate

114 N-(1-benzylpiperidin- 4-yl)-5-(1-(4- cyanobenzyl)piperidin-4-yloxy)benzofuran- 2-carboxamide

115 N-(1- isonicotinoylpiperidin- 4-yl)-5- (1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

116 N-(1-benzylpiperidin- 4-yl)-5-(1-(4- carbamoylbenzyl) piperidin-4-yloxy)benzofuran- 2-carboxamide

117 N-methyl-N-(1-(pyridin-2- ylmethyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

118 N-(1- isonicotinoylpiperidin- 4-yl)- N-methyl-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

119 N-methyl-N-(1-(4- (trifluoromethyl) benzyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

120 (R)-tert-butyl 3-(5-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)benzofuran-2- carboxamido)pyrrolidine-1- carboxylate

121 (R)-N-(pyrrolidin- 3-yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

122 (R)-N-(1-(pyridin-4- ylmethyl)pyrrolidin- 3-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

123 (R)-N-(1-(pyridin-3- ylmethyl)pyrrolidin- 3-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

124 (R)-N-(1-(pyridin-2- ylmethyl)pyrrolidin- 3-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

125 (R)-N-(1- isonicotinoylpyrrolidin-3- yl)-5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

126 (R)-N-(1-(pyridin-3- ylsulfonyl)pyrrolidin- 3-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzofuran- 2-carboxamide

127 (S)-tert-butyl 3-(5-(1-(4- chlorobenzyl)piperidin-4-yloxy)benzofuran-2- carboxamido)pyrrolidine-1- carboxylate

128 (S)-5-(1-(4- chlorobenzyl)piperidin- 4-yloxy)-N-(pyrrolidin-3-yl)benzofuran-2-carboxamide

129 (S)-5-(1-(4-chlorobenzyl) piperidin- 4-yloxy)-N-(1-(pyridin-4-ylmethyl)pyrrolidin-3- yl)benzofuran-2-carboxamide

130 (S)-5-(1-(4- chlorobenzyl)piperidin- 4-yloxy)-N-(1-(pyridin-3-ylmethyl)pyrrolidin-3- yl)benzofuran-2-carboxamide

131 5-(1-(4-carbamoylbenzyl) piperidin- 4-yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4- yl)benzofuran-2-carboxamide

132 5-(1-(4-carbamoylbenzyl) piperidin- 4-yloxy)-N-(1-isonicotinoylpiperidin-4- yl)benzofuran-2-carboxamide

133 5-(1-(4-carbamoylbenzyl) piperidin- 4-yloxy)-N-(1-(4-cyanobenzyl)piperidin-4- yl)benzofuran-2-carboxamide

134 5-(1-(4-carbamoylphenyl) piperidin- 4-yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4- yl)benzofuran-2-carboxamide

135 5-(1-(4-carbamoylphenyl) piperidin- 4-yloxy)-N-(1-isonicotinoylpiperidin-4- yl)benzofuran-2-carboxamide

136 5-(1-(4-carbamoylphenyl) piperidin- 4-yloxy)-N-(1-(4-cyanobenzyl)piperidin-4- yl)benzofuran-2-carboxamide

137 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethoxy) phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2-carboxamide

138 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-5-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2-carboxamide

139 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-5-(1-(4-chlorophenyl)piperidin-4- yloxy)benzo[b]thiophene-2- carboxamide

140 tert-butyl 4-(6-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)benzo[b]thiophene-2- carboxamido)piperidine-1- carboxylate

141 N-(piperidin-4-yl)-6-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)benzo[b]thiophene-2- carboxamide

142 N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2-carboxamide

143 N-(1-(pyridin-2- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2-carboxamide

144 N-(1-(4-cyanobenzyl) piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide

145 N-(1-(3-cyanobenzyl) piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide

146 N-(1-(2-cyanobenzyl) piperidin-4- yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide

147 tert-butyl 4-(3-chloro-6-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)benzo[b]thiophene-2- carboxamido)piperidine-1- carboxylate

148 3-chloro-N-(piperidin- 4-yl)-6-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2- carboxamide

149 tert-butyl 4-(5-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)benzo[b]thiophene-2- carboxamido)piperidine-1- carboxylate

150 N-(piperidin-4-yl)-5-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)benzo[b]thiophene-2- carboxamide

151 3-chloro-N-(1-(pyridin-4- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2-carboxamide

152 3-chloro-N-(1-(pyridin-3- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2-carboxamide

153 3-chloro-N-(1-(pyridin-2- ylmethyl)piperidin- 4-yl)-6-(1-(4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2-carboxamide

154 3-chloro-N-(1-(4- cyanobenzyl) piperidin-4-yl)-6-(1- (4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2-carboxamide

155 3-chloro-N-(1- isonicotinoylpiperidin- 4-yl)-6-(1- (4-(trifluoromethyl) phenyl)piperidin- 4-yloxy)benzo[b]thiophene-2-carboxamide

156 tert-butyl 4-(5-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)-2,3- dihydro-1H-inden-1- ylamino)piperidine- 1-carboxylate

157 N-(5-(1-(4- (trifluoromethyl) phenyl)piperidin- 4-yloxy)-2,3-dihydro-1H-inden-1- yl)piperidin-4-amine

158 1-(pyridin-4- ylmethyl)-N-(5-(1-(4- (trifluoromethyl)phenyl)piperidin- 4-yloxy)-2,3-dihydro- 1H-inden-1- yl)piperidin-4-amine

159 1-(4-fluorobenzyl)- N-(5-(1-(4- (trifluoromethyl) phenyl)piperidin-4-yloxy)-2,3- dihydro-1H-inden-1- yl)piperidin-4-amine

160 4-((4-(5-(1-(4- (trifluoromethyl) phenyl)piperidin- 4-yloxy)-2,3-dihydro-1H-inden-1- ylamino)piperidin-1- yl)methyl)benzonitrile

For simplicity, chemical moieties are defined and referred to throughoutprimarily as univalent chemical moieties (e.g., alkyl, aryl, etc.).Nevertheless, such terms are also used to convey correspondingmultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, while an “alkyl” moietycan refer to a monovalent radical (e.g. CH₃—CH₂—), in some circumstancesa bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” (Similarly, incircumstances in which a divalent moiety is required and is stated asbeing “aryl,” those skilled in the art will understand that the term“aryl” refers to the corresponding divalent moiety, arylene). All atomsare understood to have their normal number of valences for bondformation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S,depending on the oxidation state of the S). Nitrogens in the presentlydisclosed compounds can be hypervalent, e.g., an N-oxide ortetrasubstituted ammonium salt. On occasion a moiety may be defined, forexample, as (A)_(a)-B-, wherein a is 0 or 1. In such instances, when ais 0 the moiety is B- and when a is 1 the moiety is A-B-.

As used herein, the term “alkyl” includes alkyl, alkenyl and alkynylgroups of a designed number of carbon atoms, desirably from 1 to about12 carbons (i.e., inclusive of 1 and 12). The term “C_(m)-C_(n) alkyl”means an alkyl group having from m to n carbon atoms (i.e., inclusive ofm and n). The term “C_(m)-C_(n) alkyl” means an alkyl group having fromm to n carbon atoms. For example, “C₁-C₆ alkyl” is an alkyl group havingfrom one to six carbon atoms. Alkyl and alkyl groups may be straight orbranched and depending on context, may be a monovalent radical or adivalent radical (i.e., an alkylene group). In the case of an alkyl oralkyl group having zero carbon atoms (i.e., “C₀ alkyl”), the group issimply a single covalent bond if it is a divalent radical or is ahydrogen atom if it is a monovalent radical. For example, the moiety“—(C₀-C₆ alkyl)-Ar” signifies connection of an optionally substitutedaryl through a single bond or an alkylene bridge having from 1 to 6carbons. Examples of “alkyl” include, for example, methyl, ethyl,propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl,heptyl, 3-ethylbutyl, 3-hexenyl and propargyl. If the number of carbonatoms is not specified, the subject “alkyl” or “alkyl” moiety has from 1to 12 carbons.

The term “haloalkyl” is an alkyl group substituted with one or morehalogen atoms, e.g. F, Cl, Br and I. A more specific term, e.g.,“fluoroalkyl” is an alkyl group substituted with one or more fluorineatoms. Examples of “fluoroalkyl” include fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, hexafluoroisopropyl and the like. Incertain embodiments of the compounds disclosed herein, each haloalkyl isa fluoroalkyl.

The term “aryl” represents an aromatic carbocyclic ring system having asingle ring (e.g., phenyl) which is optionally fused to other aromatichydrocarbon rings or non-aromatic hydrocarbon rings. “Aryl” includesring systems having multiple condensed rings and in which at least oneis aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl). Examples ofaryl groups include phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl,dihydronaphthyl, fluorenyl, tetralinyl, 2,3-dihydrobenzofuranyl and6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. The aryl groups herein areunsubstituted or, when specified as “optionally substituted”, can unlessstated otherwise be substituted in one or more substitutable positionswith various groups, as described below.

The term “heteroaryl” refers to an aromatic ring system containing atleast one heteroatom selected from nitrogen, oxygen and sulfur in anaromatic ring. The heteroaryl may be fused to one or more cycloalkyl orheterocycloalkyl rings. Examples of heteroaryl groups include, forexample, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl,indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl,naphthyridinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, pteridinyl,benzothiazolyl, imidazopyridinyl, imidazothiazolyl,dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, chromonyl,chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl,dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl,dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl,pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinylN-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide,isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide,phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolylN-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide,benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide,oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolylN-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide.Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl,indolyl, pyrrolyl, furanyl, thienyl and imidazolyl, pyrazolyl,indazolyl, thiazolyl and benzothiazolyl. In certain embodiments, eachheteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, isothiazolyl, pyridinyl-N-oxide, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, imidazolylN-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide,pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolylN-oxide, and tetrazolyl N-oxide. Preferred heteroaryl groups includepyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl,imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. Theheteroaryl groups herein are unsubstituted or, when specified as“optionally substituted”, can unless stated otherwise be substituted inone or more substitutable positions with various groups, as describedbelow.

The term “heterocycloalkyl” refers to a non-aromatic ring or ring systemcontaining at least one heteroatom that is preferably selected fromnitrogen, oxygen and sulfur, wherein said heteroatom is in anon-aromatic ring. The heterocycloalkyl may be saturated (i.e., aheterocycloalkyl) or partially unsaturated (i.e., a heterocycloalkenyl).The heterocycloalkyl ring is optionally fused to other heterocycloalkylrings and/or non-aromatic hydrocarbon rings and/or phenyl rings. Incertain embodiments, the heterocycloalkyl groups have from 3 to 7members in a single ring. In other embodiments, heterocycloalkyl groupshave 5 or 6 members in a single ring. Examples of heterocycloalkylgroups include, for example, azabicyclo[2.2.2]octyl (in each case also“quinuclidinyl” or a quinuclidine derivative), azabicyclo[3.2.1]octyl,morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinylS,S-dioxide, 2-oxazolidonyl, piperazinyl, homopiperazinyl,piperazinonyl, pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl,tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl,3,4-dihydroisoquinolin-2(1H)-yl, isoindolindionyl, homopiperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,imidazolidonyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxideand homothiomorpholinyl S-oxide. Especially desirable heterocycloalkylgroups include morpholinyl, 3,4-dihydroisoquinolin-2(1H)-yl,tetrahydropyranyl, piperidinyl, aza-bicyclo[2.2.2]octyl,γ-butyrolactonyl (i.e., an oxo-substituted tetrahydrofuranyl),γ-butryolactamyl (i.e., an oxo-substituted pyrrolidine), pyrrolidinyl,piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, thiomorpholinylS,S-dioxide, 2-oxazolidonyl, imidazolidonyl, isoindolindionyl,piperazinonyl. The heterocycloalkyl groups herein are unsubstituted or,when specified as “optionally substituted”, can unless stated otherwisebe substituted in one or more substitutable positions with variousgroups, as described below.

The term “cycloalkyl” refers to a non-aromatic carbocyclic ring or ringsystem, which may be saturated (i.e., a cycloalkyl) or partiallyunsaturated (i.e., a cycloalkenyl). The cycloalkyl ring optionally fusedto or otherwise attached (e.g., bridged systems) to other cycloalkylrings. Preferred cycloalkyl groups have from 3 to 7 members in a singlering. More preferred cycloalkyl groups have 5 or 6 members in a singlering. Examples of cycloalkyl groups include, for example, cyclohexyl,cyclopentyl, cyclobutyl, cyclopropyl, tetrahydronaphthyl andbicyclo[2.2.1]heptane. The cycloalkyl groups herein are unsubstitutedor, when specified as “optionally substituted”, may be substituted inone or more substitutable positions with various groups.

The term “oxa” means a divalent oxygen radical in a chain, sometimesdesignated as —O—.

The term “oxo” means a doubly bonded oxygen, sometimes designated as ═Oor for example in describing a carbonyl “C(O)” may be used to show anoxo substituted carbon.

The term “electron withdrawing group” means a group that withdrawselectron density from the structure to which it is attached than would asimilarly-attached hydrogen atom. For example, electron withdrawinggroups can be selected from the group consisting of halo, cyano, —(C₁-C₄fluoroalkyl), —O—(C₁-C₄ fluoroalkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), —S(O)₂O—(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca includes a nitrogen atom to which the —C(O)—is bound, in which no alkyl, fluoroalkyl or heterocycloalkyl issubstituted with an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group.

The term “substituted,” when used to modify a specified group orradical, means that one or more hydrogen atoms of the specified group orradical are each, independently of one another, replaced with the sameor different substituent groups as defined below.

Substituent groups for substituting for hydrogens on saturated carbonatoms in the specified group or radical are, unless otherwise specified,—R⁶⁰, halo, —O⁻M⁺, ═O, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, ═S, —NR⁸⁰R⁸⁰, ═NR⁷⁰,═N—OR⁷⁰, trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃,—SO₂R⁷⁰, —SO₂O⁻M⁺, —SO₂OR⁷⁰, —OSO₂R⁷⁰, —OSO₂O⁻M⁺, —OSO₂OR⁷⁰,—P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰,—C(NR⁷⁰)R⁷⁰, —C(O)O⁻M⁺, —C(O)OR⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OC(O)O⁻M⁺, —OC(O)OR⁷⁰,—OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰,—NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰. Each R⁶⁰ is independently selected from the groupconsisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl andheteroarylalkyl, each of which is optionally substituted with 1, 2, 3, 4or 5 groups selected from the group consisting of halo, —O⁻M⁺, ═O,—OR⁷¹, —SR⁷¹, —S⁻M⁺, ═S, —NR⁸¹R⁸¹, ═NR⁷¹, ═N—OR trihalomethyl, —CF₃,—CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —SO₂R⁷¹, —SO₂O⁻M⁺, —SO₂OR⁷¹,—OSO₂R⁷¹, —OSO₂O⁻M⁺, —OSO₂OR⁷¹, —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷¹)O⁻M⁺,—P(O)(OR⁷¹)₂, —C(O)R⁷¹, —C(S)R⁷¹, —C(NR⁷¹)R⁷¹, —C(O)O⁻M⁺, —C(O)OR⁷¹,—C(S)OR⁷¹, —C(O)NR⁸¹R⁸¹, —C(NR⁷¹)NR⁸¹R⁸¹, —OC(O)R⁷¹, —OC(S)R⁷¹,—OC(O)O⁻M⁺, —OC(O)OR⁷¹, —OC(S)OR⁷¹, —NR⁷¹C(O)R⁷¹, —NR⁷¹C(S)R⁷¹, —NR⁷¹CO₂⁻M⁺, —NR⁷¹CO₂R⁷¹, —NR⁷¹C(S)OR⁷¹, —NR⁷¹C(O)NR⁸¹R⁸¹, —NR⁷¹C(NR⁷¹)R⁷¹ and—NR⁷¹C(NR⁷¹)NR⁸¹R⁸¹. Each R⁷⁰ is independently hydrogen or R⁶⁰; each R⁸⁰is independently R⁷⁰ or alternatively, two R⁸⁰'s, taken together withthe nitrogen atom to which they are bonded, form a 5-, 6- or 7-memberedheterocycloalkyl which may optionally include from 1 to 4 of the same ordifferent additional heteroatoms selected from the group consisting ofO, N and S, of which N may have —H or C₁-C₃ alkyl substitution; and eachM⁺ is a counter ion with a net single positive charge. Each R⁷¹ isindependently hydrogen or R⁶¹, in which R⁶¹ is alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkylalkyl,aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which isoptionally substituted with 1, 2, 3, 4 or 5 groups selected from thegroup consisting of halo, —O⁻M⁺, ═O, —OR⁷², —SR⁷², —S⁻M⁺, ═S, —NR⁸²R⁸²,═NR⁷², ═N—OR⁷², trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂,—N₃, —SO₂R⁷¹, —SO₂O⁻M⁺, —SO₂OR⁷², —OSO₂R⁷², —OSO₂O⁻M⁺, —OSO₂OR⁷²,—P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷²)O⁻M⁺, —P(O)(OR⁷²)₂, —C(O)R⁷², —C(S)R⁷²,—C(NR⁷²)R⁷², —C(O)O⁻, M⁺, —C(O)OR⁷², —C(S)OR⁷², —C(O)NR⁸²R⁸²,—C(NR⁷²)NR⁸²R⁸², —OC(O)R⁷², —OC(S)R⁷², —OC(O)O⁻M⁺, —OC(O)OR⁷²,—OC(S)OR⁷², —NR⁷²C(O)R⁷², —NR⁷²C(S)R⁷², —NR⁷²CO₂ ⁻M⁺, —NR⁷²CO₂R⁷²,—NR⁷²C(S)OR⁷², —NR⁷²C(O)NR⁸²R⁸², —NR⁷²C(NR⁷²)R⁷² and—NR⁷²C(NR⁷²)NR⁸²R⁸²; and each R⁸¹ is independently R⁷¹ or alternatively,two R⁸¹s, taken together with the nitrogen atom to which they arebonded, form a 5-, 6- or 7-membered heterocycloalkyl which mayoptionally include from 1 to 4 of the same or different additionalheteroatoms selected from the group consisting of O, N and S, of which Nmay have —H or C₁-C₃ alkyl substitution. Each R⁷² is independentlyhydrogen, (C₁-C₆ alkyl) or (C₁-C₆ fluoroalkyl); each R⁸² isindependently R⁷² or alternatively, two R⁸²s, taken together with thenitrogen atom to which they are bonded, form a 5-, 6- or 7-memberedheterocycloalkyl which may optionally include 1, 2, 3 or 4 of the sameor different additional heteroatoms selected from the group consistingof O, N and S, of which N may have —H or C₁-C₃ alkyl substitution. EachM⁺ may independently be, for example, an alkali ion, such as K⁺, Na⁺,Li⁺; an ammonium ion, such as ⁺N(R⁶⁰)₄; or an alkaline earth ion, suchas [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5) (“subscript 0.5 meanse.g. that one of the counter ions for such divalent alkali earth ionscan be an ionized form of a presently disclosed compound and the other atypical counter ion such as chloride, or two ionized presently disclosedmolecules can serve as counter ions for such divalent alkali earth ions,or a doubly ionized compound can serve as the counter ion for suchdivalent alkali earth ions). As specific examples, —NR⁸⁰R⁸⁰ is meant toinclude —NH₂, —NH-alkyl, N-pyrrolidinyl, N-piperazinyl,4-methyl-piperazin-1-yl and N-morpholinyl.

Substituent groups for hydrogens on unsaturated carbon atoms in“substituted” alkene, alkyne, aryl and heteroaryl groups are, unlessotherwise specified, —R⁶⁰, halo, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰,trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —SO₂R⁷⁰, —SO₃ ⁻M⁺,—SO₃R⁷⁰, —OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃ ⁷⁰, —PO₃ ⁻²(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺,—P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰,—C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺,—NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ are as previouslydefined.

Substituent groups for hydrogens on nitrogen atoms in “substituted”heteroalkyl and heterocycloalkyl groups are, unless otherwise specified,—R⁶⁰, —O⁻M⁺, —OR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰, trihalomethyl, —CF₃, —CN, —NO,—NO₂, —S(O)₂R⁷⁰, —S(O)₂O⁻M⁺, —S(O)₂OR⁷⁰, —OS(O)₂R⁷⁰, —OS(O)₂O⁻M⁺,—OS(O)₂OR⁷⁰, —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)(OR⁷⁰),—C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —C(O)OR⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OC(O)OR⁷⁰, —OC(S)OR⁷⁰,—NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰C(O)OR⁷⁰, —NR⁷⁰C(S)OR⁷⁰,—NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰, R⁷⁰,R⁸⁰ and M⁺ are as previously defined.

In certain embodiments of the compounds disclosed herein, a group thatis substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents,1 or 2 substituents, or 1 substituent.

The compounds disclosed herein can also be provided as pharmaceuticallyacceptable salts. The term “pharmaceutically acceptable salts” or “apharmaceutically acceptable salt thereof” refer to salts prepared frompharmaceutically acceptable non-toxic acids or bases including inorganicacids and bases and organic acids and bases. If the compound is basic,salts may be prepared from pharmaceutically acceptable non-toxic acids.Such salts may be, for example, acid addition salts of at least one ofthe following acids: benzenesulfonic acid, citric acid, α-glucoheptonicacid, D-gluconic acid, glycolic acid, lactic acid, malic acid, malonicacid, mandelic acid, phosphoric acid, propanoic acid, succinic acid,sulfuric acid, tartaric acid (d, l, or dl), tosic acid (toluenesulfonicacid), valeric acid, palmitic acid, pamoic acid, sebacic acid, stearicacid, lauric acid, acetic acid, adipic acid, carbonic acid,4-chlorobenzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid,fumaric acid, galactaric acid (mucic acid), D-glucuronic acid,2-oxo-glutaric acid, glycerophosphoric acid, hippuric acid, isethionicacid (ethanolsulfonic acid), lactobionic acid, maleic acid,1,5-naphthalene-disulfonic acid, 2-naphthalene-sulfonic acid, pivalicacid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecylsulfate, 3-hydroxy-2-naphthoic acid, 1-hydroxy-2-naphthoic acid, oleicacid, undecylenic acid, ascorbic acid, (+)-camphoric acid,d-camphorsulfonic acid, dichloroacetic acid, ethanesulfonic acid, formicacid, hydriodic acid, hydrobromic acid, hydrochloric acid,methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalicacid, picric acid, L-pyroglutamic acid, saccharine, salicylic acid,gentisic acid, and/or 4-acetamidobenzoic acid.

The compounds described herein can also be provided in prodrug form.“Prodrug” refers to a derivative of an active compound (drug) thatrequires a transformation under the conditions of use, such as withinthe body, to release the active drug. Prodrugs are frequently, but notnecessarily, pharmacologically inactive until converted into the activedrug. Prodrugs are typically obtained by masking a functional group inthe drug believed to be in part required for activity with a progroup(defined below) to form a promoiety which undergoes a transformation,such as cleavage, under the specified conditions of use to release thefunctional group, and hence the active drug. The cleavage of thepromoiety can proceed spontaneously, such as by way of a hydrolysisreaction, or it can be catalyzed or induced by another agent, such as byan enzyme, by light, by acid, or by a change of or exposure to aphysical or environmental parameter, such as a change of temperature.The agent can be endogenous to the conditions of use, such as an enzymepresent in the cells to which the prodrug is administered or the acidicconditions of the stomach, or it can be supplied exogenously. A widevariety of progroups, as well as the resultant promoieties, suitable formasking functional groups in the active drugs to yield prodrugs arewell-known in the art. For example, a hydroxyl functional group can bemasked as a sulfonate, ester or carbonate promoiety, which can behydrolyzed in vivo to provide the hydroxyl group. An amino functionalgroup can be masked as an amide, carbamate, imine, urea, phosphenyl,phosphoryl or sulfenyl promoiety, which can be hydrolyzed in vivo toprovide the amino group. A carboxyl group can be masked as an ester(including silyl esters and thioesters), amide or hydrazide promoiety,which can be hydrolyzed in vivo to provide the carboxyl group. Otherspecific examples of suitable progroups and their respective promoietieswill be apparent to those of skill in the art.

The compounds disclosed herein can also be provided as solvates,hydrates or N-oxides.

Compounds can be assayed for binding to a membrane-bound adiponectinreceptor by performing a competitive binding assay with adiponectin. Inone such procedure, HEK 293 cellular membrane is coated onto a COSTAR384 plate, which is then blocked with 1% casein. Polyhistidine-taggedglobular adiponectin and a candidate compound is incubated with themembrane in HEPES buffer. Unbound ligands are washed away and the degreeof binding of the adiponectin is determined using horseradishperoxidase-conjugated anti-polyhistidine. Compounds that compete withadiponectin binding to the membrane (i.e., give a reduced signalcompared to a control performed without a candidate compound) can bechosen as hits and further screened using the below-described functionalassays to identify adiponectin receptor agonists.

An in-cell western assay can be performed to demonstrate the activationof AMPK in human liver cells by globular adiponectin using glutathioneS-transferase (GST). AMPK activity can be measured by the relativeconcentration of phosphorylated acetyl Co-A carboxylase, which is one ofthe products of AMPK. An increase in pACC correlates with an increase inthe rate of fatty acid oxidation.

The compounds of structural formulae (I)-(XCIV) can be administered, forexample, orally, topically, parenterally, by inhalation or spray orrectally in dosage unit formulations containing one or morepharmaceutically acceptable carriers, diluents or excipients. The termparenteral as used herein includes percutaneous, subcutaneous,intravascular (e.g., intravenous), intramuscular, or intrathecalinjection or infusion techniques and the like.

Pharmaceutical compositions can be made using the presently disclosedcompounds. For example, in one embodiment, a pharmaceutical compositionincludes a pharmaceutically acceptable carrier, diluent or excipient,and compound as described above with reference to structural formulae(I)-(XCIV).

In the pharmaceutical compositions disclosed herein, one or morecompounds of structural formulae (I)-(XCIV) may be present inassociation with one or more pharmaceutically acceptable carriers,diluents or excipients, and, if desired, other active ingredients. Thepharmaceutical compositions containing compounds of structural formulae(I)-(XCIV) may be in a form suitable for oral use, for example, astablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsion, hard or soft capsules, or syrups orelixirs.

Compositions intended for oral use can be prepared according to anysuitable method for the manufacture of pharmaceutical compositions andsuch compositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreservative agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients that aresuitable for the manufacture of tablets. These excipients can be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets can be uncoated or they can be coated by known techniques. Insome cases such coatings can be prepared by suitable techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed.

Formulations for oral use can also be presented as hard gelatincapsules, wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

Formulations for oral use can also be presented as lozenges.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients can be suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents such as a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions can be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, can also be present.

Pharmaceutical compositions can also be in the form of oil-in-wateremulsions. The oily phase can be a vegetable oil or a mineral oil ormixtures of these. Suitable emulsifying agents can benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions can also containsweetening and flavoring agents.

Syrups and elixirs can be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations can also contain a demulcent, a preservative, flavoring,and coloring agents. The pharmaceutical compositions can be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension can be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation can also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that can beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils can be employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid find use in the preparation of injectables.

Compounds of structural formulae (I)-(XCIV) can also be administered inthe form of suppositories, e.g., for rectal administration of the drug.These compositions can be prepared by mixing the compound with asuitable non-irritating excipient that is solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum to release the drug. Such materials include cocoa butter andpolyethylene glycols.

Compounds of structural formula (I)-(XCIV) can also be administeredparenterally in a sterile medium. The drug, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

The compounds disclosed herein can be made using procedures familiar tothe person of ordinary skill in the art and as described herein. Forexample, compounds of structural formulae (II)-(VI) can be preparedaccording to Scheme 1, below, or analogous synthetic schemes:

Referring to Scheme 1, bromide 1, for example, is coupled with4-hydroxypiperidine 2 to provide 1-substituted 4-hydroxypiperidine 3. Ina separate reaction, protected Hca-amine 5 is deprotected and coupledwith chloropiperidinecarboxylic acid 4 to provide chloropyridineamide 6,which is then coupled with 3 under Mitsonobu conditions to yield4-(piperidin-4-yloxy)pyridineamide 7.

One of ordinary skill in the art can adapt the reaction sequence ofScheme 1 to fit the desired target molecule. For example, a benzylbromide can be used as a starting material to afford compounds in whichthe “A” ring system is a phenyl and Q is methylene. Similarly, a(heteroaryl)methyl bromide may be used as a starting material to affordcompounds in which the “A” ring system is a heteroaryl. Alternatively,reductive amination of an aryl or heteroaryl aldehyde, for example, withthe nitrogen of azacycloalkyl 2 would also afford 3. In certainsituations one of ordinary skill in the art will use different reagentsto effect one or more of the individual steps or to use protectedversions of certain of the R¹, R², R³, R⁴ and R⁵ substituents. Anexample of the synthesis of a compound according to Scheme 1 is providedbelow in Example 1.

Compounds of structural formulae (VIII)-(XIII) can be prepared accordingto Scheme 2, below, or analogous synthetic schemes:

Referring to Scheme 2, chloropyridinesulfonyl chloride 1, for example,is coupled with BOC-protected 4-aminopiperidine to provide sulfonamide2. Sulfonamide 3 is coupled with a piperidinol to form protectedN-piperidinyl sulfonamide 3, which is deprotected to yield N-piperidinylsulfonamide 4. Finally, a benzaldehyde is reductively coupled toN-piperidinyl sulfonamide 4 to provide the final product. Of course, incertain situations one of ordinary skill in the art will use differentreagents to affect one or more of the individual steps or to useprotected versions of certain of the substituents. As well, one ofordinary skill in the art would appreciate that other synthetic routesor sequence of steps can be used to make the presently disclosedcompounds. An example of the synthesis of a compound according to Scheme2 is provided below in Example 2.

Compounds of structural formulae (XIV)-(XV) can be prepared according toScheme 3, below, or analogous synthetic schemes:

Referring to Scheme 3, methoxybenzofuran ester 1, for example, isconverted to the corresponding hydroxybenzofuran carboxylic acid 2 withboron tribromide. Carboxylic acid 2 is coupled with Hca amine to yieldhydroxybenzofuranamide 3. 1-Substituted 4-hydroxypiperidine 4 is coupledwith amide 3 to yield (piperidin-4-yloxy)benzofuranamide 5.

One of skill in the art can adapt the reaction sequence of Scheme 3 tofit the desired target molecule. Of course, in certain situations one ofskill in the art will use different reagents to affect one or more ofthe individual steps or to use protected versions of certain of thesubstituents. An example of the synthesis of a compound according toScheme 3 is provided below in Example 3.

Compounds of structural formulae (XVI)-(XVII) can be prepared accordingto Scheme 4, below, or analogous synthetic schemes:

Referring to Scheme 4, methoxybenzothiophene ester 1, for example, isconverted to the corresponding hydroxybenzothiophene carboxylic acid 2with boron tribromide. Carboxylic acid 2 is coupled with Hca amine toyield hydroxybenzothiophene amide 3. 1-Substituted 4-hydroxypiperidine 4is coupled with amide 3 to yield (piperidin-4-yloxy)benzothiopheneamide5.

One of skill in the art can adapt the reaction sequence of Scheme 4 tofit the desired target molecule. Of course, in certain situations one ofskill in the art will use different reagents to affect one or more ofthe individual steps or to use protected versions of certain of thesubstituents.

Compounds of structural formulae (XVIII)-(XIX) can be prepared accordingto Scheme 5, below, or analogous synthetic schemes:

Referring to Scheme 5, hydroxydihydroindenone 1, for example, is coupledwith a 1-substituted 4-hydroxypiperidine to provide(piperidin-4-yloxy)dihydroindenone 2. One of ordinary skill in the artwould appreciate that the 5-hydroxy group of 1 could be at otherpositions on the aromatic ring, e.g. at the 6-position, to make otherregiosiomeric compounds, e.g. regioisomeric versions of compound 5 wherethe ether linkage is at the 6-position instead of the 5-position.Hca-amine (shown here as a BOC-protected 4-piperidineamine) isreductively coupled to (piperidin-4-yloxy)dihydroindenone 2 to yield(piperidin-4-yloxy)dihydroindeneamine 3. Further manipulations can beperformed to provide desired substitutions. For example, in Scheme 5,BOC-protected (piperidin-4-yloxy)dihydroindeneamine 3 is deprotected,then coupled with a benzyl bromide to provide compound 5. Of course, incertain situations one of ordinary skill in the art will use differentreagents to affect one or more of the individual steps or to useprotected versions of certain of the substituents. An example of thesynthesis of a compound according to Scheme 5 is provided below inExample 5.

Compounds suitable for use in the presently disclosed pharmaceuticalcompositions include compounds of Table 1, above. These compounds can bemade according to the general schemes described above, for example usinga procedure similar to that described below in the Examples.

While not intending to be bound by theory, the inventors surmise thatcompounds of structural formulae (I)-(XCIV) are mimics of adiponectinwhich act as adiponectin receptor agonists, thereby activating the AMPKpathway. Activation of the AMPK pathway has the effect of increasingglucose uptake, decreasing glycogen synthesis and increasing fatty acidoxidation, thereby reducing glycogen, intracellular triglyceride andfatty acid concentration and causing an increase in insulin sensitivity.Because they activate the AMPK pathway, compounds of structural formulae(I)-(XCIV) should also inhibit the inflammatory processes which occurduring the early phases of atherosclerosis. Accordingly, compounds ofstructural formulae (I)-(XCIV) can be useful in the treatment of type IIdiabetes and in the treatment and prevention of atherosclerosis,cardiovascular disease, obesity and non-alcoholic fatty liver disease.

Accordingly, another aspect of the present disclosure relates to amethod of activating the AMPK pathway. According to this aspect, amethod for activating the AMPK pathway in a cell includes contacting thecell with an effective amount of a compound, pharmaceutically acceptablesalt, prodrug, solvate, hydrate, N-oxide or composition described above.

In one embodiment, a method of increasing fatty acid oxidation in a cellincludes contacting the cell with an effective amount of a compound,pharmaceutically acceptable salt, prodrug, solvate, hydrate, N-oxide orcomposition described above. Acetyl Co-A carboxylase (ACC) catalyzes theformation of malonyl Co-A, a potent inhibitor of fatty acid oxidation;phosphorylation of ACC greatly reduces its catalytic activity, therebyreducing the concentration of malonyl Co-A and increasing the rate offatty acid oxidation. Because the presently disclosed compounds canincrease the rate of phosphorylation of ACC, they can reduce theinhibition of fatty acid oxidation and therefore increase its overallrate.

In another embodiment, a method of decreasing glycogen concentration ina cell includes contacting the cell with an effective amount of acompound, pharmaceutically acceptable salt, prodrug, solvate, hydrate,N-oxide or composition described above.

In another embodiment, a method of increasing glucose uptake in a cellincludes contacting the cell with an effective amount of a compound,pharmaceutically acceptable salt, prodrug, solvate, hydrate, N-oxide orcomposition described above.

In another embodiment, a method of reducing triglyceride levels in asubject includes administering to the subject an effective amount of acompound, pharmaceutically acceptable salt, prodrug, solvate, hydrate,N-oxide or composition described above.

In another embodiment, a method of increasing insulin sensitivity of asubject includes administering to the subject an effective amount of acompound, pharmaceutically acceptable salt, prodrug, solvate, hydrate,N-oxide or composition described above.

Accordingly, the compounds and compositions disclosed herein can be usedto treat a variety of metabolic disorders. For example, in oneembodiment, a method of treating type II diabetes in a subject in needof such treatment includes administering to the subject an effectiveamount of a compound, pharmaceutically acceptable salt, prodrug,solvate, hydrate, N-oxide or composition described above. In anotherembodiment, a method of treating or preventing atherosclerosis orcardiovascular disease in a subject includes administering to thesubject an effective amount of a compound, pharmaceutically acceptablesalt, prodrug, solvate, hydrate, N-oxide or composition described above.

As described above, the compounds disclosed herein can act as activatorsof the AMPK pathway. Accordingly, in another embodiment, a methodcomprises modulating the AMPK pathway (either in vitro or in vivo) bycontacting a cell with a compound, pharmaceutically acceptable salt,prodrug, solvate, hydrate, N-oxide or composition described above, oradministering a compound, pharmaceutically acceptable salt, prodrug,solvate, hydrate, N-oxide or composition described above to a mammal(e.g., a human) in an amount sufficient to modulate the AMPK activityand study the effects thereby induced. Such methods are useful forstudying the AMPK pathway and its role in biological mechanisms anddisease states both in vitro and in vivo.

Another embodiment is the use of a compound, pharmaceutically acceptablesalt, prodrug, solvate, hydrate or N-oxide or composition as describedabove in the manufacture of a medicament for any of the therapeuticpurposes described above. For example, the medicament can be for thereduction of triglyceride levels in a subject, the treatment of type IIdiabetes in a subject, or the treatment or prevention of atherosclerosisor cardiovasclular disease in a subject.

The compounds disclosed herein can be linked to labeling agents, forexample for use in variety of experiments exploring their receptorbinding, efficacy and metabolism. Accordingly, another embodiment is alabeled conjugate comprising a compound as disclosed herein covalentlylinked to a labeling agent, optionally through a linker. Suitable linkerand labeling agents will be readily apparent to those of skill in theart upon consideration of the present disclosure. The labeling agent canbe, for example, an affinity label such as biotin or strepavidin, ahapten such as digoxigenin, an enzyme such as a peroxidase, or afluorophoric or chromophoric tag. Any suitable linker can be used. Forexample, in some embodiments, an ethylene glycol, oligo(ethylene glycol)or poly(ethylene glycol) linker is used. Other examples of linkersinclude amino acids, which can be used alone or in combination withother linker groups, such as ethylene glycol, oligoethylene glycol orpolyethylene glycol. Suitable linkers include, without limitation,single amino acids, as well as di- and tripeptides. In one embodiment,the linker includes a glycine residue. The person of skill in the artwill realize, of course, that other linkers and labeling agents can beused. In other embodiments, an alkylene chain is the linker. In otherembodiments, the linker has the structure —[(C₀-C₃ alkyl)-Y^(m)—]_(m)-,in which each Y^(m) is —O—, —N(R⁹)—, or L, and m is in the range of1-40. For example, in certain embodiments, a labeled conjugate hasstructural formula (XCV):

in which the “LINK” moiety is a linker and is optional, and the “LABEL”moiety is a labeling agent, and all other variables are as describedabove, for example with respect to structural formula (I). Any of thecompounds disclosed with respect to structural formulae (I)-(XCIV) canbe used in the labeled conjugate of structural formula (XCV).

In certain embodiments, the -(LINK)₀₋₁-(LABEL) moiety is attached the“B” ring system at a benzo or pyrido ring position meta to the alicyclicethereal oxygen. For example, in one embodiment, a labeled conjugate hasstructural formula (XCVI):

in which the “LINK” moiety is a linker and is optional, and the “LABEL”moiety is a labeling agent, and all other variables are as describedabove, for example with respect to structural formulae (XIV), (XV),(XXXII), (XXXIII), (XXXVIII)-(XLVII), (LX), (LXI), (LXVI)-(LXXIV) and(LXXXIII)-(LXXXVI).

For example, in one particular embodiment, a labeled conjugate hasstructural formula (XCVII):

in which all variables are as described above, for example with respectto structural formulae (XIV), (XV), (XXXII), (XXXIII),(XXXVIII)-(XLVII), (LX), (LXI), (LXVI)-(LXXIV) and (LXXXIII)-(LXXXVI).

The following examples are intended to further illustrate certainembodiments and are not intended to limit the scope of the invention.

EXAMPLES Example 1 (a) Synthetic ExampleN-(1-(Pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)-piperidin-4-yloxy)picolinamide(compound 43)

Step 1

A solution of t-butyl 1-(pyridin-4-ylmethyl)piperidin-4-ylcarbamate(1.80 g, 6.2 mmol) in 4M HCl/dioxane (15 mL) was allowed to stir at roomtemperature for 2 h. The resulting reaction mixture was thenconcentrated to provide a white crystalline solid, which was trituratedwith ether, filtered and dried. MS (m/z): 192 (M+H)⁺.

Step 2

The HCl salt (obtained from step 1 above) was dissolved in DMF (15 mL)and transferred to a flask containing a solution of 6-chloropicolinicacid (1.0 g, 6.3 mmol), and HATU (2.9 g, 7.6 mmol) in DMF (10 mL).N-Methylmorpholine (1.5 mL, 1.38 g, 13.6 mmol) was then added and theresulting reaction mixture was allowed to stir at room temperature underN₂ atmosphere overnight. The heterogeneous reaction mixture was thenpoured into saturated sodium bicarbonate solution (100 mL) and extractedwith ethyl acetate (3×50 mL). The combined organic layers were thenwashed with water (2×50 mL), brine (1×50 mL), dried (MgSO₄), filteredand concentrated to give a brown residue, which upon trituration withethyl ether provided6-chloro-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)picolinamide as ayellow crystalline solid (1.31 g, 64%). ¹H NMR (CDCl₃) δ 8.93-8.82 (m,2H), 8.12-8.06 (m, 1H), 7.96-7.74 (m, 5H), 7.51-7.47 (m, 1H), 4.34 (brs, 2h), 4.26 (br s, 1H), 3.63-3.47 (m, 2H), 3.16-2.92 (m, 2H), 2.60-2.40(m, 2H), 2.36-2.14 (m, 2H). MS (m/z): 331 (M+H)⁺ confirmed by LC-MS,t_(r)=3.67 min

Step 3

To a solution of 1-(4-(trifluoromethyl)phenyl)-piperidin-4-ol (0.1 g,0.4 mmol) in anhydrous DMF, NaH (60% in mineral oil, 18 mg, 0.45 mmol)was added. The mixture was allowed to stir at room temperature under N₂atmosphere for 10 min, followed by the addition of6-chloro-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)picolinamide (0.15 g,0.4 mmol). The resulting reaction mixture was then stirred with heatingat 105° C. overnight. A significant amount of starting material wasstill present and hence, an additional amount of NaH was added (82 mg,2.1 mmol). The reaction mixture was allowed to stir at 105° C. for anadditional 8 h, and quenched with saturated sodium bicarbonate solution(20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL),and the combined organic layer was washed with water (2×20 mL) and brine(1×20 mL), dried (MgSO₄), filtered and concentrated to give a yellowresidue. Column chromatography (100% CH₂Cl₂→3% MeOH/CH₂Cl₂) provided ayellow solid, which upon trituration with ethyl ether, yieldedN-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamideas a tan solid (54 mg, 25%). ¹H NMR (CD₃OD) δ 8.53 (d, J=4.1 Hz, 2H),8.28 (d, J=7.4 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H),7.51 (d, J=4.1 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.3 Hz, 2H),6.96 (d, J=8.3 Hz, 1H), 5.43 (br s, 1H), 4.10-3.95 (m, 1H), 3.90 (s,2H), 3.77-3.56 (m, 2H), 3.23-2.98 (m, 3H), 2.71-2.57 (m, 2H), 2.23-1.81(m, 9H). MS (m/z): 540 (M+H)⁺.

(b) Analytical Data

The following compounds were prepared using methods analogous to thosedescribed in Example 1(a) and in Scheme 1.

Compound 1: ¹H NMR (CDCl₃, 300 MHz) δ 8.54 (m, 2H), 8.20 (m, 1H), 8.14(m, 1H), 7.77 (m, 1H), 7.50 (m, 2H), 7.29 (m, 3H), 6.89 (m, 2H), 4.65(m, 1H), 3.99 (m, 1H), 3.63 (m, 2H), 3.52 (s, 2H), 3.35 (m, 2H), 2.83(m, 2H), 2.23 (m, 2H), 2.03 (m, 6H), 1.66 (m, 2H) ppm; MS (ES) 497.5(M+H).

Compound 2: ¹H NMR (CDCl₃, 300 MHz) δ 8.20 (m, 2H), 8.13 (m, 1H), 7.77(m, 1H), 7.61 (m, 2H), 7.47 (m, 4H), 7.30 (m, 1H), 6.89 (m, 2H), 4.66(m, 1H), 3.98 (m, 1H), 3.60 (m, 4H), 3.35 (m, 2H), 2.81 (m, 2H), 2.23(m, 2H), 2.04 (m, 6H), 1.62 (m, 2H) ppm; MS (ES) 521.6 (M+H).

Compound 3: ¹H NMR (CDCl₃, 300 MHz) δ 8.54 (m, 2H), 8.20 (m, 1H), 8.13(m, 1H), 7.77 (m, 1H), 7.49 (m, 2H), 7.29 (m, 3H), 6.95 (m, 2H), 4.63(m, 1H), 3.99 (m, 1H), 3.60 (m, 2H), 3.52 (s, 2H), 3.27 (m, 2H), 2.82(m, 2H), 2.23 (m, 2H), 2.06 (m, 6H), 1.66 (m, 2H) ppm; MS (ES) 540.5(M+H).

Compound 4: ¹H NMR (CDCl₃, 300 MHz) δ 8.20 (m, 1H), 8.12 (m, 1H), 7.77(m, 1H), 7.61 (m, 2H), 7.47 (m, 4H), 7.30 (m, 1H), 6.95 (m, 2H), 4.63(m, 1H), 3.99 (m, 1H), 3.58 (m, 4H), 3.27 (m, 2H), 2.80 (m, 2H),2.31-1.88 (m, 8H), 1.64 (m, 2H) ppm; MS (ES) 564.5 (M+H).

Compound 5: ¹H NMR (CDCl₃, 300 MHz) δ 8.53 (m, 2H), 8.20 (m, 1H), 8.13(m, 1H), 7.77 (m, 1H), 7.66 (m, 1H), 7.48 (m, 2H), 7.29 (m, 2H), 6.95(m, 2H), 4.63 (m, 1H), 3.99 (m, 1H), 3.59 (m, 2H), 3.53 (s, 2H), 3.27(m, 2H), 2.84 (m, 2H), 2.27-1.88 (m, 8H), 1.64 (m, 2H) ppm; MS (ES)540.6 (M+H).

Compound 6: ¹H NMR (CDCl₃, 300 MHz) δ 8.54 (m, 2H), 8.20 (m, 1H), 8.13(m, 1H), 7.76 (m, 1H), 7.66 (m, 1H), 7.50 (m, 2H), 7.29 (m, 2H), 6.89(m, 2H), 4.65 (m, 1H), 3.98 (m, 1H), 3.63 (m, 2H), 3.53 (s, 2H), 3.35(m, 2H), 2.83 (m, 2H), 2.22 (m, 2H), 2.03 (m, 6H), 1.63 (m, 2H) ppm; MS(ES) 497.6 (M+H).

Compound 7: ¹H NMR (CDCl₃, 300 MHz) δ 8.20 (m, 1H), 8.13 (m, 1H), 7.99(m, 2H), 7.76 (m, 1H), 7.50 (m, 2H), 7.40 (m, 2H), 7.30 (m, 1H), 6.89(m, 2H), 4.66 (m, 1H), 3.99 (m, 1H), 3.91 (s, 3H), 3.63 (m, 2H), 3.56(s, 2H), 3.33 (m, 2H), 2.83 (m, 2H), 2.21 (m, 2H), 2.04 (m, 6H), 1.64(m, 2H) ppm; MS (ES) 554.6 (M+H).

Compound 8: ¹H NMR (CDCl₃, 300 MHz) δ 8.20 (m, 1H), 8.13 (m, 1H), 7.98(m, 1H), 7.77 (m, 1H), 7.48 (m, 2H), 7.41 (m, 2H), 7.309 (m, 1H), 6.95(m, 2H), 4.62 (m, 1H), 3.97 (m, 1H), 3.91 (s, 3H), 3.580 (m, 4H), 3.27(m, 2H), 2.83 (m, 2H), 2.27-1.89 (m, 8H), 1.64 (m, 2H) ppm; MS (ES)597.6 (M+H).

Compound 9: ¹H NMR (CDCl₃, 300 MHz) δ 8.52 (s, 1H), 7.96 (m, 1H), 7.46(m, 2H), 6.94 (m, 2H), 6.74 (m, 1H), 5.82 (d, J=7.5 Hz, 1H), 5.32 (m,1H), 4.02 (m, 2H), 3.62 (m, 2H), 3.24 (m, 2H), 2.83 (m, 2H), 2.27-1.76(m, 8H), 1.59 (m, 2H), 1.46 (s, 9H) ppm; MS (ES) 549.5 (M+H).

Compound 10: ¹H NMR (CDCl₃, 300 MHz) δ 8.54 (m, 3H), 7.96 (m, 1H), 7.47(m, 2H), 7.28 (m, 2H), 6.95 (m, 2H), 6.75 (m, 1H), 5.85 (d, J=7.5 Hz,1H), 5.32 (m, 1H), 4.01 (m, 1H), 3.62 (m, 2H), 3.52 (s, 2H), 3.24 (m,2H), 2.83 (m, 2H), 2.27-1.76 (m, 8H), 1.59 (m, 2H) ppm; MS (ES) 540.6(M+H).

Compound 11: ¹H NMR (CDCl₃, 300 MHz) δ 8.52 (s, 1H), 7.96 (m, 1H), 7.47(m, 2H), 7.29 (m, 2H), 6.98 (m, 4H), 6.73 (m, 1H), 5.81 (d, J=7.8 Hz,1H), 5.32 (m, 1H), 3.99 (m, 1H), 3.62 (m, 2H), 3.47 (s, 2H), 3.24 (m,2H), 2.82 (m, 2H), 2.22-1.84 (m, 8H), 1.54 (m, 2H) ppm; MS (ES) 557.6(M+H).

Compound 12: ¹H NMR (CDCl₃, 300 MHz) δ 8.32 (m, 1H), 8.01 (m, 1H), 7.74(m, 1H), 7.47 (m, 2H), 6.93 (m, 3H), 4.74 (m, 1H), 3.99 (m, 1H), 3.56(m, 2H), 3.26 (m, 2H), 2.84 (m, 2H), 2.34-1.79 (m, 8H), 1.65 (m, 2H),1.46 (s, 9H) ppm; MS (ES) 549.6 (M+H).

Compound 13: ¹H NMR (CDCl₃, 300 MHz) δ 8.54 (m, 2H), 8.34 (m, 1H), 8.00(m, 1H), 7.72 (m, 1H), 7.48 (m, 2H), 7.27 (m, 2H), 6.93 (m, 3H), 4.74(m, 1H), 3.99 (m, 1H), 3.58 (m, 2H), 3.52 (s, 2H), 3.27 (m, 2H), 2.83(m, 2H), 2.31-1.78 (m, 8H), 1.66 (m, 2H) ppm; MS (ES) 540.6 (M+H).

Compound 14: ¹H NMR (CDCl₃, 300 MHz) δ 8.48 (m, 4H), 7.67 (m, 1H), 7.47(m, 2H), 7.27 (m, 2H), 6.95 (m, 2H), 6.07 (d, J=7.5 Hz, 1H), 4.63 (m,1H), 4.03 (m, 1H), 3.60 (m, 2H), 3.53 (s, 2H), 3.25 (m, 2H), 2.85 (m,2H), 2.24 (m, 2H), 2.18-1.88 (m, 6H), 1.62 (m, 2H) ppm; MS (ES) 540.6(M+H).

Compound 15: ¹H NMR (CDCl₃, 300 MHz) δ 7.74 (m, 3H), 7.51 (m, 2H), 6.98(m, 2H), 6.88 (m, 1H), 5.21 (m, 1H), 4.02 (m, 1H), 3.60 (m, 2H), 3.31(m, 2H), 2.80 (m, 2H), 2.35-1.91 (m, 8H), 1.64 (m, 2H), 1.46 (s, 9H)ppm; MS (ES) 549.3 (M+H).

Compound 16: ¹H NMR (CDCl₃, 300 MHz) δ 8.44 (m, 2H), 7.66 (m, 1H), 7.48(m, 2H), 7.28 (m, 2H), 6.98 (m, 4H), 5.97 (d, J=7.5 Hz, 1H), 4.63 (m,1H), 4.01 (m, 1H), 3.60 (m, 2H), 3.48 (s, 2H), 3.25 (m, 2H), 2.83 (m,2H), 2.22-1.91 (m, 8H), 1.56 (m, 2H) ppm; MS (ES) 557.6 (M+H).

Compound 17: ¹H NMR (CDCl₃, 300 MHz) δ 8.48 (m, 1H), 8.42 (m, 1H), 7.64(m, 3H), 7.48 (m, 4H), 6.95 (m, 2H), 4.63 (m, 1H), 4.05 (m, 1H), 3.60(m, 4H), 3.25 (m, 2H), 2.87 (m, 2H), 2.27 (m, 2H), 2.18-1.88 (m, 6H),1.54 (m, 2H) ppm; MS (ES) 564.5 (M+H).

Compound 18: ¹H NMR (CDCl₃, 300 MHz) δ 8.51 (m, 4H), 7.69 (m, 2H), 7.48(m, 2H), 7.28 (m, 1H), 6.95 (m, 2H), 6.17 (d, J=7.8 Hz, 1H), 4.63 (m,1H), 4.03 (m, 1H), 3.61 (m, 4H), 3.25 (m, 2H), 2.89 (m, 2H), 2.25 (m,2H), 2.18-1.88 (m, 6H), 1.66 (m, 2H) ppm; MS (ES) 540.6 (M+H).

Compound 19: ¹H NMR (CD₃OD, 300 MHz) δ 7.80 (m, 6H), 7.14 (m, 1H), 7.07(m, 1H), 5.79 (m, 1H), 4.19 (m, 1H), 3.91-3.44 (m, 6H), 3.16 (m, 2H),2.43 (m, 2H), 2.11 (m, 7H) ppm; MS (ES) 449.7 (M+H).

Compound 20: ¹H NMR (CDCl₃, 300 MHz) δ 8.53 (m, 2H), 7.70 (m, 3H), 7.49(m, 2H), 7.28 (m, 2H), 6.97 (m, 2H), 6.89 (m, 1H), 5.22 (m, 1H), 4.01(m, 1H), 3.61 (m, 2H), 3.52 (s, 2H), 3.30 (m, 2H), 2.81 (m, 2H),2.31-1.94 (m, 8H), 1.63 (m, 2H) ppm; MS (ES) 540.6 (M+H).

Compound 21: ¹H NMR (CDCl₃, 300 MHz) δ 7.75 (m, 2H), 7.59 (m, 3H), 7.46(m, 4H), 6.98 (m, 2H), 6.89 (m, 1H), 5.22 (m, 1H), 3.99 (m, 1H), 3.59(m, 2H), 3.55 (s, 2H), 3.29 (m, 2H), 2.78 (m, 2H), 2.21 (m, 4H), 2.03(m, 4H), 1.62 (m, 2H) ppm; MS (ES) 564.6 (M+H).

Compound 22: ¹H NMR (CDCl₃, 300 MHz) δ 7.76 (m, 3H), 7.49 (m, 2H), 7.28(m, 2H), 6.99 (m, 4H), 6.87 (m, 1H), 5.20 (m, 1H), 4.01 (m, 1H), 3.61(m, 2H), 3.47 (s, 2H), 3.29 (m, 2H), 2.80 (m, 2H), 2.18 (m, 4H), 2.01(m, 4H), 1.56 (m, 2H) ppm; MS (ES) 557.6 (M+H).

Compound 23: ¹H NMR (CDCl₃, 300 MHz) δ 8.20 (m, 2H), 8.13 (m, 1H), 7.92(m, 1H), 7.50 (m, 2H), 7.31 (m, 1H), 7.01 (m, 2H), 4.65 (m, 2H), 3.71(m, 1H), 3.64-3.22 (m, 7H), 2.21 (m, 3H), 2.01 (m, 3H), 1.46 (s, 9H)ppm; MS (ES) 535.2 (M+H).

Compound 24: ¹H NMR (CD₃OD, 300 MHz) δ 8.50 (m, 1H), 8.22 (m, 1H), 7.85(m, 3H), 7.61 (m, 2H), 5.04 (m, 1H), 4.68 (m, 1H), 3.92 (m, 2H),3.77-3.52 (m, 4H), 3.41 (m, 2H), 2.42 (m, 3H), 2.25 (m, 2H) ppm; MS (ES)435.6 (M+H).

Compound 25: ¹H NMR (CDCl₃, 300 MHz) δ 8.54 (m, 2H), 8.20 (m, 1H), 8.11(m, 2H), 7.48 (m, 2H), 7.31 (m, 3H), 6.96 (m, 2H), 4.63 (m, 2H), 3.68(s, 2H), 3.60 (m, 2H), 3.26 (m, 2H), 2.72 (m, 2H), 2.42 (m, 2H), 2.11(m, 3H), 1.98 (m, 3H) ppm; MS (ES) 526.6 (M+H).

Compound 44: ¹H NMR (CDCl₃, 300 MHz) 9.16 (m, 1H), 8.77 (m, 2H), 8.20(m, 1H), 8.12 (m, 1H), 7.80 (m, 1H), 7.48 (m, 2H), 7.29 (m, 1H), 6.95(m, 2H), 4.63 (m, 1H), 4.01 (m, 1H), 3.59 (m, 4H), 3.27 (m, 2H), 2.92(m, 2H), 2.35 (m, 2H), 2.04 (m, 6H), 1.76 (m, 2H) ppm; MS (ES) 541.9(M+H).

Compound 45: ¹H NMR (CDCl₃, 300 MHz) 8.52 (m, 1H), 7.98 (m, 2H), 7.43(m, 4H), 7.28 (m, 2H), 6.95 (m, 2H), 6.76 (m, 1H), 5.83 (m, 1H), 5.32(m, 1H), 3.93 (m, 5H), 3.59 (m, 4H), 3.24 (m, 2H), 2.84 (m, 2H), 2.04(m, 8H) ppm; MS (ES) 597.8 (M+H).

Compound 46: ¹H NMR (CD₃OD, 300 MHz) 8.62 (m, 1H), 8.12 (m, 3H), 7.64(m, 2H), 7.46 (m, 2H), 7.06 (m, 2H), 6.82 (m, 1H), 5.32 (m, 1H), 4.41(m, 2H), 4.15 (m, 1H), 3.66 (m, 2H), 3.51 (m, 2H), 3.26 (m, 4H), 2.19(m, 4H), 1.89 (m, 4H) ppm; MS (ES) 583.6 (M+H).

Compound 47: ¹H NMR (CDCl₃, 300 MHz) 8.16 (m, 2H), 7.74 (m, 1H), 7.48(m, 1H), 7.32 (m, 12H), 7.13 (m, 6H), 6.95 (m, 2H), 6.18 (m, 1H), 4.61(m, 1H), 3.94 (m, 1H), 3.54 (m, 4H), 3.27 (m, 2H), 2.87 (m, 2H), 2.21(m, 4H), 1.97 (m, 4H), 1.25 (m, 2H) ppm; MS (ES) 529.6 (M+H).

Compound 48: ¹H NMR (CD₃OD, 300 MHz) 9.09 (m, 1H), 8.50 (m, 1H), 8.20(m, 1H), 7.95 (m, 1H), 7.82 (m, 5H), 4.59 (m, 1H), 4.20 (m, 1H), 3.81(m, 8H), 2.47 (m, 2H), 2.21 (m, 8H) ppm; MS (ES) 529.7 (M+H).

Compound 49: ¹H NMR (CDCl₃, 300 MHz) 8.12 (m, 3H), 7.52 (m, 2H), 7.22(m, 1H), 6.94 (m, 2H), 5.10 (m, 1H), 4.62 (m, 1H), 3.55 (m, 3H), 3.24(m, 3H), 2.11 (m, 2H), 1.97 (m, 2H), 1.76 (m, 4H), 1.44 (s, 9H) ppm; MS(ES) 523.5 (M+H).

Compound 50: ¹H NMR (CDCl₃, 300 MHz) 8.22 (m, 5H), 7.60 (m, 4H), 7.25(m, 1H), 6.91 (m, 2H), 4.9 (m, 1H), 4.63 (m, 1H), 3.52 (m, 5H), 3.22 (m,3H), 2.13 (m, 2H), 1.95 (m, 2H), 1.73 (m, 4H) ppm; MS (ES) 514.5 (M+H).

(c) Assay Data

Compounds 1-50 of Table 1 were assayed for their ability to activateAMPK using an enzyme-linked immunosorbent assay. The EC₅₀ values forAMPK activation for compounds 1-50 are presented in Table 2 below, inwhich “A” is less than 0.1 μM; “B” is 0.1-0.5 μM; “C” is 0.5-1 μM; “D”is 1-5 μM; “E” is 5-10 μM; and “F” is >10 μM.

TABLE 2 Cpd No. AMPK EC₅₀ 1 B 2 A 3 A 4 A 5 A 6 B 7 A 8 A 9 B 10 A 11 A12 C 13 B 14 A 15 D 16 A 17 A 18 A 19 D 20 C 21 B 22 D 23 B 24 E 25 B 26B 27 F 28 A 29 B 30 A 31 A 32 B 33 C 34 C 35 B 36 C 37 C 38 D 39 B 40 A41 B 42 D 43 D 44 B 45 F 46 D 47 D 48 D 49 A 50 D

Example 2 (a) Synthetic ExampleN-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyridine-3-sulfonamide(compound 56) Step 1. tert-butyl4-(6-chloropyridine-3-sulfonamido)piperidine-1-carboxylate

To a stirred mixture of 6-chloropyridine-3-sulfonyl chloride (1 g, 4.717mmol) in anhydrous dichloromethane (5 mL) was added triethylamine (790μl, 5.66 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (945 mg,4.717 mmol). The mixture was stirred at room temperature overnight andthen poured into water. The resulting solids were collected byfiltration to yield 1.7 g (99%) of tert-butyl4-(6-chloropyridine-3-sulfonamido)piperidine-1-carboxylate as a whitesolid. ¹H-NMR (CDCl₃, 300 MHz): δ 9.82 (s, 1H), 8.11 (dd, 1H), 7.43 (d,1H), 4.62 (d, 1H), 3.91 (m, 2H), 3.36 (m, 1H), 2.80 (m, 2H), 3.97 (m,1H), 1.81 (m, 2H), 1.40 (s, 9H), 1.18 (m, 2H); LCMS: MS (m/z): 376(MH⁺).

Step 2. tert-butyl4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyridine-3-sulfonamido)piperidine-1-carboxylate

To a stirred solution of 1-(4-(trifluoromethyl)phenyl)piperidin-4-ol(1.4 g, 5.71 mmol) in dimethylormamide (10 mL) at room temperature wasadded sodium hydride slowly (0.5 g, 60%, 12.4 mmol). After effervescencesubsided, tert-butyl4-(6-chloropyridine-3-sulfonamido)piperidine-1-carboxylate (1.03 g, 4.75mmol) was added slowly. The mixture was stirred at room temperatureovernight and then poured into ice-water. The residue was purified byflash chromatography (silica gel, 2% methanol in methylene chloride) toafford the title compound as a yellow solid (2.75 g, 99%). ¹H-NMR(CDCl₃, 300 MHz): δ 8.64 (s, 1H), 7.97 (dd, 1H), 7.47 (d, 2H), 6.98 (d,2H), 6.79 (d, 1H), 5.37 (m, 1H), 4.91 (d, 1H), 3.93 (m, 2H), 3.63 (m,2H), 3.29 (m, 2H), 2.861 (m, 2H), 1.97 (m, 2H), 1.78 (m, 2H), 1.43 (s,9H), 1.41 (m, 2H); LCMS: MS (m/z): 585 (MH⁺)

Step 3.N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyridine-3-sulfonamide

The compound from step b, above, was dissolved in 4N HCl in dioxane, andstirred for 1 h at room temperature. The reaction mixture wasconcentrated to dryness. The residue (100 mg, 0.168 mmol) and4-cyanobenzaldehyde (33 mg, 0.247 mmol) were mixed in THF (5 mL) andtreated with sodium triacetoxyborohydride (70 mg, 0.328 mmol). Themixture was stirred at room temperature under N₂ overnight. The reactionmixture was quenched with 1N NaOH, and extracted with EtOAc. Thecombined organic layers were washed with brine and dried over MgSO₄. Thefinal product was purified by flash chromatography (2% MeOH/CH₂Cl₂) toafford the title compound (55 mg, 87%) as a white solid. ¹H-NMR (CDCl₃,300 MHz): δ 8.62 (s, 1H), 7.97 (dd, 1H), 7.61 (d, 2H), 7.52 (d, 2H),7.40 (d, 1H), 6.95 (d, 2H), 6.79 (d, 1H), 5.34 (m, 1H), 4.62 (m, 1H),3.63 (m, 2H), 3.52 (s, 2H), 3.26 (m, 2H), 2.72 (m, 2H), 2.12 (m, 2H),1.98 (m, 4H), 1.53 (m, 4H); LCMS: MS (m/z): 600 (MH⁺).

(b) Assay Data

Compounds 51-60 of Table 1 were assayed for their ability to activateAMPK using an enzyme-linked immunosorbent assay. The EC₅₀ values forAMPK activation for compounds 51-60 are presented in Table 3 below, inwhich “A” is less than 0.1 μM; “B” is 0.1-0.5 μM; “C” is 0.5-1 μM; “D”is 1-5 μM; “E” is 5-50 μM; and “F” is >50 μM.

TABLE 3 Cpd No. AMPK EC₅₀ 51 B 52 B 53 B 54 D 55 D 56 E 57 C 58 A 59 B60 F

Example 3 (a) Synthetic ExampleN-(1-benzylpiperidin-4-yl)-5-(1-(4-cyanobenzyl)piperidin-4-yloxy)benzofuran-2-carboxamide(compound 70) Step 1. 5-Hydroxybenzofuran-2-carboxylic acid

A solution of 5-methoxybenzofuran-2-carboxylic acid ethyl ester (5.506g, 25 mmol) in anhydrous CH₂Cl₂ (15 mL) was cooled to −40° C. under N₂atmosphere. BBr₃ (1.0 M in CH₂Cl₂, 27 mL) was added over 1 h usingdropping funnel. The reaction mixture was allowed to warm to roomtemperature. After over-night, the reaction mixture was cooled in anice-bath and quenched with brine (100 mL) and extracted with ethylacetate (3×100 mL), dried (Na₂SO₄) and concentrated. Finally dried underhigh vacuum to furnish 3.11 g (70%) of the desired product 2. ¹H NMR(DMSO-d₆, 300 MHz): δ 13.3 (s, 1H), 7.48 (m, 2H), 7.02 (s, 1H), 6.94 (m,1H); LCMS (m/z):179 (MH⁺).

Step 2. N-(1-Benzylpiperidin-4-yl)-5-hydroxybenzofurancarboxamide

To a stirred mixture of 5-hydroxybenzofuran-2-carboxylic acid (1.02 g,5.74 mmol) in anhydrous dimethylformamide (12 mL) was addedtriethylamine (0.96 mL), 1-hydroxybenzotriazole (0.91 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.33 g) and1-benzylpiperidin-4-ylamine (1.33 g). The reaction mixture was stirredat room temperature over-night and then solvents were removed underreduced pressure, poured into water, filter the solid and washed withwater. The solid was purified by silica gel column chromatography,eluted with CH₂Cl₂: MeOH (95:5) to afford 0.72 g (36%) of 3 as a whitesolid. ¹H NMR (DMSO-d₆, 300 MHz): δ 9.33 (s, 1H), 8.42 (d, J=8.1 Hz,1H), 7.40 (d, J=8.7 Hz, 1H), 7.34 (s, 1H), 7.28 (m, 5H), 6.98 (d, J=2.1Hz, 1H), 6.86 (dd, J=2.4 and 8.8 Hz, 1H), 3.74 (br s, 1H), 3.44 (s, 2H),2.80 (d, J=10.8 Hz, 2H), 1.99 (t, J=11.1 Hz, 2H), 1.99 (m, 4H), 1.66 (m,4H); LCMS (m/z): 351 (MH⁺).

Step 3.N-(1-benzylpiperidin-4-yl)-5-(1-(4-cyanobenzyl)piperidin-4-yloxy)benzofuran-2-carboxamide

To a stirred mixture ofN-(1-Benzylpiperidin-4-yl)-5-hydroxybenzofurancarboxamide (85 mg, 0.245mmol) in anhydrous toluene (3 mL) at room temperature was addeddiisopropyl azodicarboxylate (0.05 mL, 0.25 mmol),1-(4-cyanobenzyl)piperidin-4-ol (53 mg, 0.245 mmol) andtriphenylphosphine (64 mg, 0.25 mmol). The reaction was stirred at 80°C. under N₂ atmosphere overnight and then concentrated under reducedpressure. The residue thus obtained was purified by silica gel columnchromatography, eluted with CH₂Cl₂: MeOH (97:3) to afford 50 mg (37%) ofcompound 10 as a white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.48 (d,J=8.1 Hz, 1H), 7.77 (d, J=8.1 Hz, 2H), 7.50 (d, J=7.8 Hz, 3H), 7.38 (s,1H), 7.28 (m, 6H), 7.01 (d, J=8.1 Hz, 1H), 4.37 (br s, 1H), 3.76 (br s,1H), 3.57 (s, 2H), 3.44 (s, 2H), 2.80 (d, J=10.5 Hz, 2H), 2.65 (br s,2H), 2.26 (t, J=9.9 Hz, 2H), 1.99 (m, 4H), 1.66 (m, 6H); LCMS (m/z): 549(MH⁺).

(b) Analytical Data

The following compounds were prepared using methods analogous to thosedescribed in Example 3(a) and in Scheme 3.

Compound 61: tert-butyl4-(3-methyl-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamido)piperidine-1-carboxylate.¹H NMR (CDCl₃, 300 MHz) δ 7.46 (m, 2H), 7.27 (m, 1H), 6.98 (m, 4H), 6.38(d, J=7.8 Hz, 1H), 4.55 (m, 1H), 3.98 (m, 1H), 3.61 (m, 2H), 3.25 (m,2H), 2.84 (m, 2H), 2.58 (s, 3H), 2.25-1.92 (m, 8H), 1.56 (m, 2H), 1.46(s, 9H) ppm; MS (ES) 602.4 (M+H).

Compound 62:3-methyl-N-(piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide.¹H NMR (CD₃OD, 300 MHz) δ 7.61 (m, 3H), 7.37 (m, 2H), 7.18 (m, 1H), 7.06(m, 1H), 4.76 (m, 1H), 4.17 (m, 1H), 3.82-3.41 (m, 6H), 3.13 (m, 2H),2.55 (s, 3H), 2.31-1.82 (m, 9H) ppm; MS (ES) 502.5 (M+H).

Compound 63:N-(1-(4-fluorobenzyl)piperidin-4-yl)-3-methyl-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide.¹H NMR (CDCl₃, 300 MHz) δ 7.47 (m, 2H), 7.28 (m, 3H), 6.98 (m, 6H), 6.39(d, J=7.8 Hz, 1H), 4.56 (m, 1H), 3.99 (m, 1H), 3.60 (m, 2H), 3.48 (s,2H), 3.24 (m, 2H), 2.84 (m, 2H), 2.58 (s, 3H), 2.22-1.91 (m, 8H), 1.56(m, 2H) ppm; MS (ES) 610.6 (M+H).

Compound 64:N-(1-(4-cyanobenzyl)piperidin-4-yl)-3-methyl-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide.¹H NMR (CDCl₃, 300 MHz) δ 7.61 (m, 2H), 7.47 (m, 5H), 6.96 (m, 4H), 6.40(d, J=7.2 Hz, 1H), 4.56 (m, 1H), 4.01 (m, 1H), 3.58 (m, 4H), 3.28 (m,2H), 2.82 (m, 2H), 2.58 (s, 3H), 2.26-1.91 (m, 8H), 1.56 (m, 2H) ppm; MS(ES) 617.6 (M+H).

Compound 65:3-methyl-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide.¹H NMR (CD₃OD, 300 MHz) δ 8.49 (m, 2H), 7.54 (m, 1H), 7.46 (m, 4H), 7.14(m, 1H), 7.06 (m, 2H), 6.99 (m, 1H), 4.66 (m, 1H), 3.93 (m, 1H), 3.65(m, 4H), 3.25 (m, 2H), 2.95 (m, 2H), 2.53 (s, 3H), 2.28 (m, 2H), 2.13(m, 2H), 2.02-1.69 (m, 6H) ppm; MS (ES) 593.3 (M+H).

Compound 66:N-(1-(3-cyanobenzyl)piperidin-4-yl)-3-methyl-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide.¹H NMR (CD₃OD, 300 MHz) δ 7.81 (m, 1H), 7.72 (m, 2H), 7.56 (m, 2H), 7.47(m, 2H), 7.05 (m, 4H), 4.67 (m, 1H), 3.93 (m, 1H), 3.87 (s, 2H), 3.66(m, 2H), 3.26 (m, 2H), 3.12 (m, 2H), 2.54 (m, 5H), 2.18-1.74 (m, 8H)ppm; MS (ES) 617.3 (M+H).

Compound 67:N-(1-(2-cyanobenzyl)piperidin-4-yl)-3-methyl-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide.¹H NMR (CD₃OD, 300 MHz) δ 7.72 (m, 1H), 7.62 (m, 2H), 7.53 (m, 1H), 7.45(m, 3H), 7.14 (m, 1H), 7.04 (m, 2H), 6.98 (m, 1H), 4.66 (m, 1H), 3.91(m, 1H), 3.73 (s, 2H), 3.64 (m, 2H), 3.25 (m, 2H), 2.94 (m, 2H), 2.53(s, 3H), 2.29 (m, 2H), 2.11 (m, 2H), 1.90 (m, 4H), 1.74 (m, 2H) ppm; MS(ES) 617.3 (M+H);

Compound 71:N-(1-benzylpiperidin-4-yl)-5-(1-(4-cyanophenyl)piperidin-4-yloxy)benzofuran-2-carboxamideformate salt. ¹H NMR (DMSO-d₆, 300 MHz): δ 9.51 (s, 1H), 8.78 (d, J=7.2Hz, 1H), 7.47 (m, 7H), 7.33 (d, J=2.4 Hz, 1H), 7.05 (m, 3H), 4.63 (br s,1H), 4.28 (d, J=4.8 Hz, 2H), 3.99 (s, 1H), 3.71 (m, 2H), 3.37 (s, 2H),3.27 (t, J=8.7 Hz, 3H), 3.10 (m, 2H), 2.00 (m, 4H), 1.84 (m, 2H), 1.66(m, 2H); LCMS (m/z): 535 (MH⁺).

Compound 72:N-(1-benzylpiperidin-4-yl)-5-(1-(4-chlorobenzyl)piperidin-4-yloxy)benzofuran-2-carboxamide.¹H NMR (DMSO-d₆, 300 MHz): δ 8.47 (d, J=7.8 Hz, 1H), 7.49 (d, J=8.7 Hz,1H), 7.38-7.26 (m, 11H), 7.01 (dd, J=2.1 and 9.1 Hz, 1H), 4.36 (br s,1H), 3.73 (br s, 1H), 3.47 (s, 2H), 3.45 (s, 2H), 2.81 ((d, J=10.2 Hz,2H), 2.64 (m, 2H), 2.23 (t, J=9.6 Hz, 2H), 1.96 (m, 4H), 1.71 (m, 6H);LCMS (m/z): 558 (MH⁺).

Compound 73:N-(1-benzylpiperidin-4-yl)-5-(1-(3-(trifluoromethyl)benzyl)piperidin-4-yloxy)benzofuran-2-carboxamide.¹H NMR (DMSO-d₆, 300 MHz): δ 8.47 (d, J=8.1 Hz, 1H), 7.60 (m, 4H), 7.49(d, J=9.3 Hz, 1H), 7.38 (d, J=0.9 Hz, 1H), 7.27 (m, 6H), 7.02 (dd, J=2.4and 9.0 Hz, 1H), 4.38 (br s, 1H), 3.74 (br s, 1H), 3.59 (s, 2H), 3.46(s, 2H), 2.82 ((d, J=10.8 Hz, 2H), 2.66 (m, 2H), 2.27 (t, J=9.6 Hz, 2H),1.95 (m, 4H), 1.67 (m, 7H); LCMS (m/z): 592 (MH⁺).

Compound 74:N-(1-benzylpiperidin-4-yl)-5-(1-(3,4-difluorobenzyl)piperidin-4-yloxy)benzofuran-2-carboxamide.¹H NMR (DMSO-d₆, 300 MHz): δ 8.49 (d, J=8.1 Hz, 1H), 7.50 (d, J=8.7 Hz,1H), 7.33 (m, 9H), 7.14 (m, 1H), 7.02 (dd, J=2.4 and 9.0 Hz, 1H), 4.36(br s, 1H), 3.73 (br s, 1H), 3.47 (s, 2H), 3.44 (s, 2H), 2.80 (d, J=10.5Hz, 2H), 2.65 (m, 2H), 2.23 (t, J=9.0 Hz, 2H), 1.95 (m, 4H), 1.65 (m,6H); LCMS (m/z): 560 (MH⁺).

Compound 75:N-(1-benzylpiperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide.¹H NMR (DMSO-d₆, 300 MHz): δ 8.48 (d, J=7.5 Hz, 1H), 7.62-7.45 (m, 5H),7.41 (s, 1H), 7.31 (m, 5H), 7.06 (dd, J=2.7 and 9.0 Hz, 1H), 4.61 (m,1H), 3.70 (m, 3H), 3.45 (s, 2H), 3.22 (t, J=9.9 Hz, 2H), 2.81 (d, J=9.0Hz, 2H), 2.01 (m, 4H), 1.68 (m, 6H); LCMS (m/z): 578 (MH⁺).

Compound 76:N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamide.¹H NMR (DMSO-d₆, 300 MHz): δ 8.50 (m, 2H), 7.52 (d, J=9.3 Hz, 2H), 7.47(d, J=9.0 Hz, 2H), 7.41 (s, 1H), 7.31 (m, 3H), 7.07 (d, J=8.1 Hz, 3H),4.61 (m, 1H), 3.76 (m, 1H), 3.67 (m, 2H), 3.50 (s, 2H), 3.22 (t, J=9.6Hz, 2H), 2.80 (d, J=11.1 Hz, 2H), 2.04 (d, J=10.5 Hz, 4H), 1.71 (m, 6H);LCMS (m/z): 579 (MH⁺).

Compound 77:5-(1-(4-chlorobenzyl)piperidin-4-yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzofuran-2-carboxamide.¹H NMR (DMSO-d₆, 300 MHz): δ 8.49 (m, 2H), 7.49 (d, J=9.3 Hz, 2H),7.39-7.25 (m, 8H), 7.01 (dd, J=2.4 and 9.0 Hz, 1H), 4.36 (m, 1H), 3.75(m, 1H), 3.49 (s, 2H), 3.47 (s, 2H), 2.79 (d, J=11.4 Hz, 2H), 2.64 (m,2H), 2.22 (t, J=8.4 Hz, 2H), 2.05 (m, 2H), 1.92 (m, 2H), 1.65 (m, 6H);LCMS (m/z): 559 (MH⁺).

Compound 78:N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamidetrifluoroacetate salt. ¹H NMR (DMSO-d₆, 300 MHz): δ 9.76 (s, 1H), 8.78(d, J=7.5 Hz, 1H), 7.71 (d, J=6.0 Hz, 2H), 7.55 (m, 2H), 7.44 (s, 1H),7.34 (s, 1H), 7.18 (d, J=8.7 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H), 7.02 (d,J=9.0 Hz, 2H), 4.57 (s, 2H), 4.34 (s, 2H), 4.02 (m, 2H), 3.45 (m, 3H),3.09 (m, 3H), 2.03 (m, 4H), 1.85-1.71 (m, 4H); LCMS (m/z): 595 (MH⁺).

Compound 79:5-(1-(4-cyanobenzyl)piperidin-4-yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzofuran-2-carboxamide.¹H NMR (DMSO-d₆, 300 MHz): δ 8.49 (m, 2H), 7.49 (d, J=9.3 Hz, 2H),7.39-7.25 (m, 8H), 7.01 (dd, J=2.4 and 9.0 Hz, 1H), 4.36 (m, 1H), 3.75(m, 1H), 3.49 (s, 2H), 3.47 (s, 2H), 2.79 (d, J=11.4 Hz, 2H), 2.64 (m,2H), 2.22 (t, J=8.4 Hz, 2H), 2.05 (m, 2H), 1.92 (m, 2H), 1.65 (m, 6H);LCMS (m/z): 550 (MH⁺).

Compound 80:N-(1-benzylpiperidin-4-yl)-5-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamidetrifluoroacetate salt. ¹H NMR (DMSO-d₆, 300 MHz): δ 9.46 (s, 1H), 8.78(d, J=7.8 Hz, 1H), 7.47 (m, 6H), 7.33 (s, 1H), 7.16 (d, J=8.7 Hz, 2H),7.06 (dd, J=2.4 and 8.7 Hz, 1H), 7.01 (d, J=8.7 Hz, 2H), 4.57 (s, 2H),4.28 (d, J=4.8 Hz, 4H), 3.51 (m, 2H), 3.40 (d, J=11.1 Hz, 2H), 3.09 (t,J=9.6 Hz, 3H), 2.02 (m, 3H), 1.79 (m, 4H); LCMS (m/z): 594 (MH⁺).

Compound 81: tert-butyl4-(6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamido)piperidine-1-carboxylate.¹H NMR (CDCl₃, 300 MHz): δ 7.66 (m, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.45(m, 1H), 7.39 (s, 1H), 7.10 (d, J=8.7 Hz, 2H), 7.02 (s, 1H), 6.93 (m,3H), 6.40 (d, J=7.8 Hz, 1H), 6.32 (s, 1H), 4.52 (m, 1H), 4.12 (m, 3H),3.49 (m, 2H), 3.13 (m, 2H), 2.93 (t, J=12.0 Hz, 2H), 2.04 (m, 5H), 1.48(s, 9H); LCMS (m/z): 604 (MH⁺).

Compound 82: tert-butyl4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamido)piperidine-1-carboxylate.¹H NMR (DMSO-d₆, 300 MHz): δ 8.85 (s, 1H), 8.40 (d, J=7.8 Hz, 1H), 7.61(d, J=8.7 Hz, 1H), 7.46 (m, 3H), 7.26 (s, 1H), 7.07 (d, J=8.7 Hz, 2H),6.98 (d, J=8.7 Hz, 1H), 4.72 (m, 2H), 3.93 (m, 3H), 3.68 (m, 2H), 3.23(t, J=9.6 Hz, 2H), 2.81 (br s, 2H), 2.04 (m, 2H), 1.73 (m, 4H), 1.40 (s,9H); LCMS (m/z): 588 (MH⁺).

Compound 83:N-(piperidin-4-yl)-6-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamidehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.85 (s, 1H), 8.76 (br s,1H), 8.65 (d, J=7.5 Hz, 1H), 7.56 (m, 3H), 7.22 (m, 2H), 7.13 (s, 1H),6.99 (d, J=8.1 Hz, 1H), 4.71 (m, 2H), 3.55 (m, 2H), 3.30 (d, J=11.7 Hz,2H), 3.15 (t, J=8.7 Hz, 2H), 2.99 (m, 2H), 2.09 (m, 2H), 1.94 (m, 2H),1.80 (m, 3H); LCMS (m/z): 504 (MH⁺).

Compound 84:N-(piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamidehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.82 (m, 1H), 8.65 (d, J=7.5Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.49 (m, 2H), 7.27 (s, 1H), 7.08 (d,J=9.0 Hz, 2H), 6.99 (dd, J=1.5 and 8.7 Hz, 1H), 4.71 (m, 1H), 4.04 (m,1H), 3.66 (m, 2H), 3.27 (m, 3H), 2.99 (m, 2H), 2.05 (m, 2H), 1.93 (m,2H), 1.77 (m, 4H); LCMS (m/z): 488 (MH⁺).

Compound 85: tert-butyl4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamido)piperidine-1-carboxylate.¹H NMR (DMSO-d₆, 300 MHz): δ 8.53 (d, J=8.1 Hz, 1H), 7.49 (m, 4H), 7.33(d, J=2.1 Hz, 1H), 7.07 (d, J=8.7 Hz, 3H), 4.61 (m, 1H), 3.93 (m, 3H),3.67 (m, 2H), 3.22 (m, 3H), 2.81 (br s, 3H), 2.02 (m, 2H), 1.73 (m, 4H),1.40 (s, 9H); LCMS (m/z): 588 (MH⁺).

Compound 86:N-(piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzofuran-2-carboxamidehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.84 (m, 1H), 8.77 (d, J=7.5Hz, 1H), 7.70 (m, 1H), 7.49 (m, 3H), 7.34 (s, 1H), 7.08 (d, J=9.0 Hz,3H), 4.62 (m, 1H), 4.05 (m, 1H), 3.66 (m, 2H), 3.27 (m, 3H), 2.99 (m,2H), 1.97 (m, 4H), 1.78 (m, 4H); LCMS (m/z): 488 (MH⁺).

Compound 87: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.49 (d, J=5.1 Hz, 2H), 8.37(d, J=8.4 Hz, 1H), 7.61 (d, J=9.0 Hz, 1H), 7.46 (m, 3H), 7.29 (m, 3H),7.07 (d, J=8.7 Hz, 2H), 6.98 (d, J=8.4 Hz, 1H), 4.70 (m, 1H), 4.68 (m,3H), 3.50 (s, 1H), 3.23 (t, J=9.9 Hz, 2H), 2.79 (t, J=11.7 Hz, 2H), 2.06(t, J=9.3 Hz, 4H), 1.69 (m, 6H); LCMS (m/z): 579 (MH⁺).

Compound 88: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.48 (d, J=5.4 Hz, 2H), 8.36(d, J=7.8 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.44 (s, 1H), 7.30 (d, J=5.7Hz, 2H), 7.26 (s, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.00 (m, 3H), 4.66 (m,1H), 3.75 (m, 1H), 3.56 (m, 2H), 3.50 (s, 2H), 3.10 (t, J=9.0 Hz, 2H),2.79 (d, J=11.1 Hz, 2H), 2.06 (t, J=9.3 Hz, 4H), 1.69 (m, 6H); LCMS(m/z): 595 (MH⁺).

Compound 89: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.35 (d, J=8.1 Hz, 1H), 7.78(d, J=8.4 Hz, 2H), 7.56 (m, 3H), 7.43 (s, 1H), 7.26 (s, 1H), 7.16 (d,J=8.4 Hz, 2H), 7.00 (m, 3H), 4.65 (br s, 1H), 3.74 (br s, 1H), 3.55 (s,2H), 3.50 (m, 2H), 3.10 (t, J=9.3 Hz, 2H), 2.79 (d, J=11.1 Hz, 2H), 2.06(t, J=10.8 Hz, 4H), 1.74 (m, 4H), 1.63 (m, 2H); LCMS (m/z): 619 (MH⁺).

Compound 90: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.36 (d, J=7.8 Hz, 1H), 7.78(d, J=8.1 Hz, 2H), 7.60 (d, J=8.7 Hz, 1H), 7.48 (m, 4H), 7.27 (s, 1H),7.07 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.1 Hz, 1H), 4.70 (br s, 1H), 3.68(br s, 3H), 3.55 (s, 2H), 3.23 (t, J=10.2 Hz, 3H), 2.78 (d, J=11.7 Hz,2H), 2.06 (t, J=10.5 Hz, 4H), 1.69 (m, 6H); LCMS (m/z): 603 (MH⁺).

Compound 91: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.35 (d, J=7.8 Hz, 2H), 7.60(d, J=9.0 Hz, 1H), 7.46 (t, J=9.0 Hz, 3H), 7.30 (m, 3H), 7.09 (m, 4H),6.97 (dd, J=2.1 and 8.4 Hz, 1H), 4.70 (m, 1H), 3.67 (m, 3H), 3.43 (s,2H), 3.26 (m, 2H), 2.79 (d, J=11.4 Hz, 2H), 2.03 (m, 4H), 1.71-1.54 (m,6H); LCMS (m/z): 596 (MH⁺).

Compound 92: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.46 (d, J=4.8 Hz, 1H), 7.37(d, J=8.1 Hz, 1H), 7.74 (t, J=7.5 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.44(s, 1H), 7.41 (d, J=7.5 Hz, 1H), 7.24 (m, 2H), 7.16 (d, J=8.7 Hz, 2H),6.99 (m, 3H), 4.66 (m, 1H), 3.77 (m, 1H), 3.57 (s, 2H), 3.52 (m, 2H),2.09 (t, J=9.3 Hz, 2H), 2.83 (d, J=11.7 Hz, 2H), 2.09 (t, J=9.9 Hz, 4H),1.73 (m, 6H); LCMS (m/z): 595 (MH⁺).

Compound 93: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.46 (d, J=4.8 Hz, 1H), 7.37(d, J=7.8 Hz, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.44(m, 4H), 7.27 (s, 1H), 7.23 (d, J=7.2 Hz, 1H), 7.07 (d, J=8.7 Hz, 2H),6.98 (d, J=8.7 Hz, 1H), 4.70 (m, 1H), 3.71 (m, 3H), 3.57 (s, 2H), 2.23(t, J=9.9 Hz, 2H), 2.83 (d, J=11.4 Hz, 2H), 2.09 (t, J=9.9 Hz, 4H), 1.69(m, 6H); LCMS (m/z): 579 (MH⁺).

Compound 94: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.36 (d, J=7.8 Hz, 1H), 7.58(m, 4H), 7.43 (s, 1H), 7.29 (m, 2H), 7.14 (m, 3H), 6.99 (m, 2H), 4.65(m, 1H), 3.74 (m, 1H), 3.51 (m, 2H), 3.43 (s, 2H), 3.09 (t, J=10.2 Hz,2H), 2.79 (d, J=11.1 Hz, 2H), 1.99 (t, J=11.1 Hz, 4H), 1.72 (m, 4H),1.61 (m, 2H); LCMS (m/z): 612 (MH⁺).

Compound 95: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.50 (s, 3H), 7.72 (s, 1H),7.61 (d, J=8.7 Hz, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 7.25 (s, 1H), 7.16(d, J=8.4 Hz, 2H), 7.00 (t, J=9.3 Hz, 3H), 4.65 (s, 1H), 3.79 (m, 1H),3.53 (m, 2H), 3.39 (s, 2H), 3.09 (t, J=9.3 Hz, 3H), 2.82 (m, 2H), 2.04(m, 3H), 1.73 (m, 6H); LCMS (m/z): 595 (MH⁺).

Compound 96: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.47 (s, 1H), 8.44 (d, J=4.2Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.60 (d, J=9.0Hz, 1H), 7.47 (d, J=8.7 Hz, 2H), 7.43 (s, 1H), 7.33 (dd, J=4.8 and 7.6Hz, 2H), 7.26 (s, 1H), 7.07 (d, J=8.7 Hz, 2H), 6.97 (dd, J=1.8 and 8.5Hz, 2H), 4.70 (m, 1H), 3.68 (m, 2H), 3.49 (s, 2H), 3.25 (m, 3H), 2.80(d, J=11.7 Hz, 2H), 2.03 (t, J=10.2 Hz, 4H), 1.73-1.57 (m, 6H); LCMS(m/z): 579 (MH⁺).

Compound 97: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.37 (d, J=7.8 Hz, 1H), 7.79(d, J=7.5 Hz, 1H), 7.69-7.54 (m, 4H), 7.44 (m, 2H), 7.26 (s, 1H), 7.16(d, J=9.0 Hz, 1H), 6.99 (m, 3H), 4.65 (m, 2H), 3.76 (m, 1H), 3.63 (s,2H), 3.54 (m, 2H), 3.09 (t, J=10.5 Hz, 2H), 2.81 (d, J=11.1 Hz, 2H),2.10 (m, 4H), 1.74 (m, 4H), 1.62 (s, 2H); LCMS (m/z): 619 (MH⁺).

Compound 98: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.37 (d, J=8.4 Hz, 1H), 7.79(d, J=7.5 Hz, 1H), 7.69-7.53 (m, 4H), 7.44 (m, 3H), 7.27 (s, 1H), 7.07(d, J=8.7 Hz, 2H), 6.96 (d, J=8.4 Hz, 1H), 4.73 (m, 1H), 3.70 (m, 2H),3.63 (s, 2H), 3.25 (m, 3H), 2.81 (d, J=11.4 Hz, 2H), 2.10 (m, 4H),1.73-1.59 (m, 6H); LCMS (m/z): 603 (MH⁺).

Compound 99: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.34 (d, J=7.5 Hz, 1H), 7.67(d, J=7.5 Hz, 2H), 7.61 (d, J=9.0 Hz, 1H), 7.49 (m, 5H), 7.26 (s, 1H),7.07 (d, J=8.7 Hz, 2H), 6.97 (d, J=8.4 Hz, 1H), 4.70 (m, 1H), 3.68 (m,3H), 3.55 (s, 2H), 3.23 (t, J=9.6 Hz, 2H), 2.80 (d, J=10.5 Hz, 2H), 2.06(t, J=10.5 Hz, 4H), 1.74-1.61 (m, 6H); LCMS (m/z): 646 (MH⁺).

Compound 100: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.50 (d, J=7.8 Hz, 1H), 7.67(d, J=6.9 Hz, 2H), 7.51 (m, 5H), 7.41 (s, 1H), 7.33 (s, 1H), 7.07 (d,J=8.7 Hz, 3H), 4.61 (m, 1H), 3.70 (m, 3H), 3.55 (s, 2H), 3.22 (t, J=10.2Hz, 2H), 2.80 (d, J=10.5 Hz, 2H), 2.05 (m, 4H), 1.74-1.61 (m, 6H); LCMS(m/z): 646 (MH⁺).

Compound 101: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.47 (s, 3H), 7.68 (d, J=8.1Hz, 1H), 7.49 (m, 3H), 7.41 (s, 1H), 7.33 (m, 2H), 7.05 (m, 3H), 4.61(m, 1H), 3.70 (m, 3H), 3.49 (s, 2H), 3.22 (m, 2H), 2.80 (d, J=10.8 Hz,2H), 2.03 (m, 4H), 1.72-1.59 (m, 6H); LCMS (m/z): 579 (MH⁺).

Compound 102: ¹H NMR (DMSO-d₆, 300 MHz): δ 7.54 (d, J=8.7 Hz, 1H), 7.47(d, J=8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.4 Hz, 3H), 4.61(m, 1H), 4.03 d, J=10.2 Hz, 2H), 3.68 (m, 2H), 3.22 (t, J=10.2 Hz, 2H),2.98 (s, 3H), 2.02 (br s, 2H), 1.68 (m, 5H), 1.40 (s, 9H); LCMS (m/z):602 (MH⁺).

Compound 103: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.91 (s, 1H), 7.55 (d, J=9.0Hz, 1H), 7.48 (d, J=8.1 Hz, 2H), 7.31 (s, 2H), 7.08 (m, 3H), 4.61 (m,1H), 3.668 (m, 2H), 3.33 (d, J=11.1 Hz, 2H), 3.23 (t, J=9.6 Hz, 2H),3.01 (br s, 5H), 2.05 (m, 4H), 1.83 (m, 2H), 1.71 (m, 3H); LCMS (m/z):502 (MH⁺).

Compound 104: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.48 (d, J=4.5 Hz, 2H), 7.53(d, J=9.0 Hz, 1H), 7.47 (d, J=8.7 Hz, 2H), 7.30 (s, 3H), 7.24 (s, 1H),7.06 (m, 3H), 4.61 (m, 1H), 3.66 (m, 2H), 3.50 (s, 2H), 3.22 (t, J=10.8Hz, 2H), 3.01 (m, 2H), 2.86 (d, J=10.5 Hz, 2H), 2.48 (s, 4H), 2.06 (m,3H), 1.87 (m, 2H), 1.67 (m, 3H); LCMS (m/z): 593 (MH⁺).

Compound 105: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.50 (m, 2H), 7.52 (d, J=9.3Hz, 2H), 7.47 (d, J=9.0 Hz, 2H), 7.41 (s, 1H), 7.31 (m, 3H), 7.07 (d,J=8.1 Hz, 3H), 4.61 (m, 1H), 3.76 (m, 1H), 3.67 (m, 2H), 3.50 (s, 2H),3.22 (t, J=9.6 Hz, 2H), 2.80 (d, J=11.1 Hz, 2H), 2.04 (d, J=10.5 Hz,4H), 1.71 (m, 6H); LCMS (m/z): 579 (MH⁺).

Compound 106: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.89 (m, 2H), 8.45 (d, J=7.8Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.68 (dd, J=5.1 and 8.2 Hz, 1H), 7.60(d, J=7.8 Hz, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.42 (s, 1H), 7.25 (s, 1H),7.07 (d, J=8.7 Hz, 2H), 6.98 (dd, J=1.5 and 8.5 Hz, 1H), 4.70 (m, 1H),3.78 (m, 1H), 3.68 (d, J=12.0 Hz, 4H), 3.23 (t, J=9.9 Hz, 2H), 2.03 (m,2H), 1.85 (d, J=10.5 Hz, 2H), 1.65 (m, 6H); LCMS (m/z): 629 (MH⁺).

Compound 107: ¹H NMR (DMSO-d₆, 300 MHz): δ 7.77 (d, J=8.4 Hz, 2H), 7.50(m, 5H), 7.30 (s, 1H), 7.25 (s, 1H), 7.06 (m, 3H), 4.60 (m, 1H), 3.69(m, 2H), 3.55 (s, 2H), 3.31 (s, 3H), 3.22 (t, J=10.2 Hz, 2H), 3.02 (m,2H), 2.85 (d, J=9.9 Hz, 2H), 2.02 (m, 3H), 1.87 (m, 2H), 1.68 (m, 4H);LCMS (m/z): 617 (MH⁺).

Compound 108: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.89 (m, 2H), 8.45 (d, J=7.5Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.68 (dd, J=5.1 and 8.2 Hz, 1H), 7.59(m, 2H), 7.42 (s, 1H), 7.24 (s, 1H), 7.16 (d, J=9.0 Hz, 1H), 7.00 (m,3H), 4.66 (m, 1H), 3.81 (m, 1H), 3.68 (d, J=11.7 Hz, 2H), 3.53 (m, 2H),3.09 (t, J=9.9 Hz, 2H), 2.05 (m, 3H), 1.85 (d, J=12.6 Hz, 2H), 1.75-1.60(m, 4H); LCMS (m/z): 645 (MH⁺).

Compound 109: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.45 (m, 2H), 7.68 (d, J=8.1Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 2H), 7.30 (m, 3H),7.06 (m, 3H), 4.60 (m, 1H), 3.67 (m, 2H), 3.49 (s, 2H), 3.31 (s, 3H),3.22 (m, 4H), 3.01 (m, 2H), 2.88 (d, J=6.9 Hz, 2H), 2.02 (m, 2H), 1.85(m, 2H), 1.68 (m, 2H); LCMS (m/z): 593 (MH⁺).

Compound 110: ¹H NMR (DMSO-d₆, 300 MHz): δ 7.71 (d, J=7.8 Hz, 2H), 7.64(d, J=8.4 Hz, 1H), 7.53 (d, J=9.0 Hz, 2H), 7.47 (d, J=9.0 Hz, 2H), 7.30(d, J=2.1 Hz, 1H), 7.24 (s, 1H), 7.06 (m, 3H), 4.61 (m, 1H), 3.67 (m,2H), 3.52 (s, 2H), 3.31 (s, 3H), 3.22 (t, J=9.6 Hz, 2H), 3.02 (s, 2H),2.86 (d, J=9.0 Hz, 2H), 2.02 (m, 3H), 1.87 (m, 2H), 1.68 (m, 4H); LCMS(m/z): 617 (MH⁺).

Compound 111: ¹H NMR (DMSO-d₆, 300 MHz): δ 7.79 (d, J=7.5 Hz, 1H), 7.66(t, J=7.8 Hz, 1H), 7.56 (d, J=8.1 Hz, 2H), 7.46 (m, 3H), 7.30 (s, 1H),7.25 (s, 1H), 7.06 (m, 3H), 4.61 (m, 1H), 3.68 (m, 1H), 3.63 (s, 2H),3.31 (s, 3H), 3.22 (t, J=9.9 Hz, 2H), 2.99 (m, 2H), 2.88 (d, J=9.9 Hz,2H), 2.13 (m, 2H), 2.04 (m, 2H), 1.81 (m, 2H), 1.67 (m, 4H); LCMS (m/z):617 (MH⁺).

Compound 112: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.66 (d, J=5.7 Hz, 2H), 8.42(d, J=7.8 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.47 (d, J=10.2 Hz, 3H), 7.34(d, J=6.0 Hz, 2H), 7.26 (s, 1H), 7.07 (d, J=8.7 Hz, 2H), 6.99 (dd, J=2.1and 8.5 Hz, 1H), 4.71 (m, 1H), 4.44 (d, J=13.2 Hz, 1H), 4.06 (m, 1H),3.68 (m, 2H), 3.44 (m, 2H), 3.24 (m, 3H), 2.95 (m, 1H), 2.04 (m, 2H),1.90 (m, 1H), 1.73 (m, 3H), 1.54 (m, 1H); LCMS (m/z): 593 (MH⁺).

Compound 113: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.511 (d, J=8.4 Hz, 1H), 7.77(d, J=8.1 Hz, 2H), 7.50 (m, 3H), 7.39 (s, 1H), 7.26 (s, 1H), 7.02 (dd,J=2.4 and 8.8 Hz, 1H), 4.38 (m, 1H), 3.93 (d, J=12.0 Hz, 3H), 3.57 (s,2H), 2.80 (m, 2H), 2.65 (m, 2H), 2.26 (t, J=9.6 Hz, 3H), 1.93 (m, 2H),1.72 (m, 4H), 1.46 (m, 1H), 1.40 (s, 9H); LCMS (m/z): 559 (MH⁺).

Compound 114: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.49 (d, J=7.8 Hz, 1H), 7.77(d, J=8.4 Hz, 2H), 7.49 (m, 3H), 7.39 (s, 1H), 7.28 (m, 6H), 7.02 (dd,J=2.1 and 8.8 Hz, 1H), 4.38 (m, 1H), 3.73 (m, 1H), 3.57 (s, 2H), 3.44(s, 2H), 2.80 (d, J=10.2 Hz, 2H), 2.64 (m, 2H), 2.25 (t, J=9.3 Hz, 2H),1.95 (m, 4H), 1.66 (m, 6H); LCMS (m/z): 549 (MH⁺).

Compound 115: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.66 (d, J=4.5 Hz, 2H), 8.57(d, J=7.8 Hz, 1H), 7.49 (m, 4H), 7.35 (m, 3H), 7.07 (d, J=8.4 Hz, 1H),4.61 (m, 1H), 4.45 (d, J=13.5 Hz, 1H), 4.08 (m, 1H), 3.65 (m, 1H), 3.45(d, J=12.9 Hz, 1H), 3.22 (t, J=11.4 Hz, 3H), 2.94 (m, 1H), 2.02 (m, 2H),1.90 (d, J=11.7 Hz, 1H), 1.79-1.49 (m, 6H); LCMS (m/z): 593 (MH⁺).

Compound 116: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.63 (s, 1H), 8.52 (s, 1H),7.92 (s, 1H), 7.81 (d, J=7.8 Hz, 2H), 7.49 (d, J=9.0 Hz, 2H), 7.30 (m,8H), 7.02 (d, J=7.8 Hz, 1H), 4.37 (m, 1H), 4.77 (m, 1H), 3.53 (s, 2H),3.45 (s, 2H), 3.12 (m, 1H), 2.81 (br s, 1H), 2.67 (br s, 2H), 2.25 (brs, 2H), 1.94 (m, 4H), 1.66 (m, 6H); LCMS (m/z): 567 (MH⁺).

Compound 117: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.46 (d, J=4.2 Hz, 1H), 7.74(t, J=7.5 Hz, 1H), 7.47 (m, 4H), 7.25 (m, 3H), 7.06 (m, 3H), 4.61 (m,1H), 3.68 (m, 2H), 3.58 (s, 2H), 3.31 (s, 3H), 3.21 (t, J=9.3 Hz, 2H),3.04 (br s, 1H), 2.91 (d, J=10.5 Hz, 2H), 2.08 (m, 4H), 1.87 (m, 2H),1.68 (m, 4H); LCMS (m/z): 593 (MH⁺).

Compound 118: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.65 (d, J=5.7 Hz, 2H), 7.54(d, J=8.4 Hz, 1H), 7.47 (d, J=8.7 Hz, 2H), 7.42 (d, J=5.7 Hz, 2H), 7.49(d, J=8.4 Hz, 4H), 7.30 (d, J=2.7 Hz, 2H), 7.06 (m, 3H), 4.61 (m, 2H),3.68 (m, 2H), 3.47 (m, 1H), 3.28 (s, 3H), 3.22 (t, J=10.5 Hz, 2H), 3.05(m, 2H), 2.88 (m, 1H), 2.02 (m, 4H), 1.81 (m, 2H), 1.70 (m, 4H); LCMS(m/z): 607 (MH⁺).

Compound 119: ¹H NMR (DMSO-d₆, 300 MHz): δ 7.67 (d, J=7.8 Hz, 2H), 7.52(m, 5H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (s, 1H), 7.06 (m, 3H), 4.61 (m,1H), 3.68 (m, 2H), 3.55 (s, 2H), 3.29 (s, 3H), 3.22 (t, J=9.3 Hz, 2H),3.00 (s, 2H), 2.87 (d, J=9.9 Hz, 2H), 2.02 (m, 3H), 1.87 (m, 2H), 1.69(m, 4H); LCMS (m/z): 660 (MH⁺).

Compound 120: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.81 (d, J=6.9 Hz, 1H), 7.49(m, 4H), 7.34 (s, 1H), 7.07 (d, J=8.7 Hz, 3H), 4.62 (m, 1H), 4.41 (m,1H), 3.65 (m, 2H), 3.52 (m, 2H), 3.37 (m, 1H), 3.22 (t, J=9.0 Hz, 4H),2.06 (m, 3H), 1.93 (m, 1H), 1.70 (m, 2H), 1.39 (s, 9H); LCMS (m/z): 574(MH⁺).

Compound 121: ¹H NMR (DMSO-d₆, 300 MHz): δ 9.14 (s, 2H), 9.00 (d, J=6.9Hz, 1H), 7.54 (t, J=4.8 Hz, 2H), 7.48 (d, J=9.0 Hz, 2H), 7.36 (d, J=2.7Hz, 1H), 7.09 (d, J=7.5 Hz, 2H), 4.62 (m, 1H), 4.58 (m, 1H), 3.48 (m,2H), 3.37 (m, 2H), 3.22 (m, 4H), 2.18 (m, 1H), 2.02 (m, 3H), 1.70 (m,2H); LCMS (m/z): 474 (MH⁺).

Compound 122: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.71 (d, J=7.5 Hz, 1H), 8.48(s, 2H), 7.49 (m, 4H), 7.34 (t, J=5.7 Hz, 3H), 7.07 (dd, J=2.4 and 8.8Hz, 3H), 4.62 (m, 1H), 4.38 (m, 1H), 3.70 (m, 1H), 3.63 (s, 2H), 3.24(m, 3H), 2.81 (m, 1H), 2.64 (m, 1H), 2.15 (m, 1H), 2.02 (m, 3H), 1.88(m, 1H), 1.70 (m, 3H); LCMS (m/z): 565 (MH⁺).

Compound 123: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.71 (d, J=7.5 Hz, 1H), 8.48(s, 2H), 7.49 (m, 4H), 7.34 (t, J=5.7 Hz, 3H), 7.07 (dd, J=2.4 and 8.8Hz, 3H), 4.62 (m, 1H), 4.38 (m, 1H), 3.70 (m, 1H), 3.63 (s, 2H), 3.24(m, 3H), 2.81 (m, 1H), 2.64 (m, 1H), 2.15 (m, 1H), 2.02 (m, 3H), 1.88(m, 1H), 1.70 (m, 3H); LCMS (m/z): 565 (MH⁺).

Compound 124: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.85 (s, 1H), 8.68 (d, J=6.6Hz, 1H), 8.46 (d, J=2.4 Hz, 1H), 7.74 (m, 1H), 7.46 (m, 4H), 7.34 (d,J=2.7 Hz, 1H), 7.23 (t, J=5.4 Hz, 1H), 7.34 (m, 2H), 7.07 (d, J=9.0 Hz,3H), 4.62 (m, 1H), 4.38 (m, 1H), 3.72 (s, 2H), 3.65 (m, 1H), 3.22 (t,J=10.5 Hz, 4H), 2.85 (m, 1H), 2.69 (m, 1H), 2.55 (m, 1H), 2.15 (m, 1H),2.02 (m, 2H), 1.83 (m, 1H), 1.70 (m, 2H); LCMS (m/z): 565 (MH⁺).

Compound 125: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.89 (m, 1H), 8.65 (m, 2H),7.47 (m, 6H), 7.35 (dd, J=2.4 and 8.1 Hz, 1H), 7.07 (m, 3H), 4.61 (m,1H), 4.42 (m, 1H), 3.66 (m, 3H), 3.52 (m, 2H), 3.22 (t, J=10.2 Hz, 3H),2.16 (m, 1H), 2.02 (m, 3H), 1.70 (m, 2H); LCMS (m/z): 579 (MH⁺).

Compound 126: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.93 (d, J=1.8 Hz, 1H), 8.68(dd, J=1.5 and 4.8 Hz, 1H), 8.61 (d, J=6.0 Hz, 1H), 8.18 (m, 1H), 7.56(m, 2H), 7.47 (d, J=9.0 Hz, 2H), 7.35 (m, 2H), 7.07 (m, 3H), 4.61 (m,1H), 4.27 (q, J=6.3 Hz, 1H), 3.68 (m, 2H), 3.46 (m, 2H), 3.23 (m, 4H),2.03 (m, 3H), 1.91 (m, 1H), 1.70 (m, 2H); LCMS (m/z): 615 (MH⁺).

Compound 127: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.78 (d, J=6.6 Hz, 1H), 7.50(d, J=9.0 Hz, 1H), 7.43 (s, 1H), 7.34 (m, 5H), 7.02 (dd, J=2.7 and 8.8Hz, 1H), 4.38 (m, 2H), 3.52 (m, 1H), 3.47 (s, 2H), 3.39 (m, 1H), 2.21(m, 2H), 2.64 (m, 2H), 2.23 (t, J=11.1 Hz, 2H), 2.06 (m, 1H), 1.92 (m,3H), 1.63 (m, 2H), 1.39 (s, 9H); LCMS (m/z): 554 (MH⁺).

Compound 128: ¹H NMR (DMSO-d₆, 300 MHz): δ 9.19 (br s, 2H), 9.02 (d,J=6.6 Hz, 1H), 7.65 (t, J=9.0 Hz, 2H), 7.55 (m, 3H), 7.36 (dd, J=2.4 and9.3 Hz, 1H), 7.15-7.04 (m, 1H), 4.74 (s, 1H), 4.54 (m, 2H), 4.34 (m,2H), 3.67 (m, 1H), 3.19 (d, J=5.7 Hz, 4H), 3.01 (t, J=11.4 Hz, 2H), 2.18(m, 3H), 2.02 (m, 3H); LCMS (m/z): 454 (MH⁺).

Compound 129: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.67 (d, J=6.9 Hz, 1H), 8.46(s, 2H), 7.49 (d, J=8.7 Hz, 1H), 7.41 (s, 1H), 7.32 (m, 6H), 7.01 (d,J=8.7 Hz, 2H), 4.37 (m, 2H), 3.62 (s, 2H), 3.47 (s, 2H), 2.80 (t, J=7.8Hz, 1H), 2.64 (d, J=5.4 Hz, 3H), 2.22 (t, J=9.9 Hz, 4H), 1.92 (m, 4H),1.65 (m, 2H); LCMS (m/z): 545 (MH⁺).

Compound 130: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.67 (d, J=7.2 Hz, 1H), 8.49(s, 1H), 7.43 (d, J=3.0 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.49 (d, J=8.7Hz, 1H), 7.33 (m, 6H), 7.01 (dd, J=2.1 and 9.1 Hz, 1H), 4.36 (m, 2H),3.61 (s, 2H), 3.47 (s, 2H), 2.77 (t, J=7.2 Hz, 1H), 2.63 (m, 2H), 2.46(m, 3H), 2.19 (m, 3H), 1.91 (m, 2H), 1.82 (m, 1H), 1.64 (m, 2H); LCMS(m/z): 545 (MH⁺).

Compound 131: LCMS (m/z): 568 (MH⁺).

(c) Assay Data

Compounds 61-131 of Table 1 were assayed for their ability to activateAMPK using an enzyme-linked immunosorbent assay. The EC₅₀ values forAMPK activation for compounds 61-131 are presented in Table 4 below, inwhich “A” is less than 0.1 μM; “B” is 0.1-0.5 μM; “C” is 0.5-1 μM; “D”is 1-10 μM; “E” is 10-50 μM and “F” is >50 μM.

TABLE 4 Cpd No. AMPK EC₅₀ 61 B 62 E 63 A 64 A 65 A 66 A 67 A 68 A 69 A70 A 71 A 72 B 73 C 74 B 75 A 76 B 77 B 78 A 79 B 80 A 81 B 82 B 83 B 84E 85 C 86 F 87 A 88 A 89 A 90 A 91 F 92 C 93 B 94 A 95 A 96 A 97 A 98 A99 A 100 A 101 A 102 D 103 D 104 B 105 A 106 B 107 A 108 B 109 A 110 A111 B 112 A 113 B 114 B 115 A 116 B 117 A 118 B 119 A 120 D 121 F 122 B123 B 124 D 125 D 126 D 127 D 128 F 129 D 130 D 131 D

Example 4 (a) Analytical Data

The following compounds were prepared using methods analogous to thosedescribed in Example 3(a) and in Scheme 4.

Compound 137:N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide.¹H NMR (DMSO-d₆, 300 MHz): δ 8.56 (m, 3H), 8.04 (s, 1H), 7.92 (d, J=8.4Hz, 1H), 7.56 (s, 1H), 7.37 (d, J=4.5 Hz, 2H), 7.21 (t, J=8.4 Hz, 3H),7.08 (d, J=9.0 Hz, 2H), 4.72 (m, 1H), 3.80 (m, 1H), 3.59 (m, 2H), 3.57(s, 2H), 3.17 (t, J=9.6 Hz, 2H), 2.89 (d, J=11.4 Hz, 2H), 2.13 (t, J=9.9Hz, 4H), 1.85 (m, 4H), 1.69 (m, 2H); LCMS (m/z): 611 (MH⁺).

Compound 138:N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide.¹H NMR (DMSO-d₆, 300 MHz): δ 8.50 (m, 3H), 7.97 (s, 1H), 7.86 (d, J=9.0Hz, 1H), 7.48 (d, J=8.4 Hz, 3H), 7.30 (d, J=5.4 Hz, 2H), 7.13 (d, J=10.8Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 4.69 (m, 1H), 3.67 (m, 3H), 3.50 (s,2H), 3.24 (t, J=9.3 Hz, 2H), 2.80 (d, J=11.7 Hz, 2H), 2.06 (t, J=9.9 Hz,4H), 1.83-1.59 (m, 6H); LCMS (m/z): 595 (MH⁺).

Compound 139:N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-chlorophenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamideformate salt. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.50 (m, 3H), 8.13 (s, 1H),7.95 (s, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.21 (d, J=1.8 Hz, 1H), 7.33 (m,5H), 7.07 (dd, J=2.1 and 9.0 Hz, 1H), 4.45 (m, 1H), 3.72 (m, 1H), 3.50(s, 2H), 3.48 (s, 2H), 2.80 (d, J=9.9 Hz, 2H), 2.67 (m, 2H), 2.25 (t,J=9.3 Hz, 2H), 2.07 (t, J=10.8 Hz, 2H), 1.94 (m, 2H), 1.80 (m, 2H), 1.63(m, 4H); LCMS (m/z): 575 (MH⁺).

Compound 140: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.85 (s, 1H), 8.43 (d, J=8.1Hz, 1H), 7.98 (s, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.66 (s, 1H), 7.47 (d,J=9.0 Hz, 2H), 7.06 (m, 3H), 4.75 (m, 2H), 3.93 (m, 3H), 3.69 (m, 2H),3.22 (t, J=9.3 Hz, 2H), 2.83 (m, 2H), 2.05 (m, 2H), 1.77 (m, 4H), 1.41(s, 9H); LCMS (m/z): 604 (MH⁺).

Compound 141: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.85 (s, 1H), 8.79 (br s,1H), 7.68 (d, J=7.2 Hz, 1H), 8.07 (s, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.66(s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.07 (m, 3H), 4.74 (m, 1H), 4.21 (s,4H), 4.01 (s, 2H), 3.79 (s, 2H), 3.68 (m, 2H), 3.27 (m, 2H), 3.01 (m,2H), 1.98 (m, 2H), 1.75 (m, 2H); LCMS (m/z): 504 (MH⁺).

Compound 142: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.49 (d, J=4.8 Hz, 2H), 8.43(d, J=7.5 Hz, 1H), 7.99 (s, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.65 (s, 1H),7.47 (d, J=9.0 Hz, 2H), 7.30 ((d, J=4.8 Hz, 2H), 7.06 (t, J=8.4 Hz, 3H),4.72 (m, 1H), 3.69 (m, 3H), 3.50 (s, 2H), 3.22 (t, J=9.6 Hz, 2H), 2.80(d, J=11.1 Hz, 2H), 2.06 (t, J=9.6 Hz, 4H), 1.82-1.58 (m, 6H); LCMS(m/z): 595 (MH⁺).

Compound 143: ¹H NMR (CDCl₃, 300 MHz): δ 8.46 (d, J=4.8 Hz, 1H), 8.42(d, J=7.8 Hz, 1H), 7.99 (s, 1H), 7.75 (m, 2H), 7.65 (d, J=1.5 Hz, 1H),7.47 (d, J=9.0 Hz, 2H), 7.41 (d, J=7.2 Hz, 1H), 7.24 (t, J=6.9 Hz, 1H),7.07 (d, J=8.7 Hz, 2H), 7.03 (d, J=2.1 Hz, 1H), 4.72 (m, 1H), 4.71 (m,2H), 3.58 (s, 2H), 3.22 (t, J=9.6 Hz, 3H), 2.84 (d, J=11.4 Hz, 2H), 2.10(m, 4H), 1.81-1.54 (s, 6H); LCMS (m/z): 595 (MH⁺).

Compound 144: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.41 (d, J=8.1 Hz, 1H), 7.99(s, 1H), 7.78 (d, J=8.1 Hz, 3H), 7.64 (s, 1H), 7.49 (d, J=8.4 Hz, 4H),7.06 (m, 3H), 4.75 (m, 1H), 3.69 (m, 1H), 3.56 (s, 2H), 3.23 (t, J=9.6Hz, 2H), 2.79 (d, J=11.4 Hz, 2H), 2.06 (m, 4H), 1.78 (m, 2H), 1.65 (m,4H); LCMS (m/z): 619 (MH⁺).

Compound 145: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.40 (d, J=7.5 Hz, 1H), 7.99(s, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.72 (m, 2H), 7.65 (d, J=2.1 Hz, 2H),7.54 (d, J=7.8 Hz, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.06 (m, 3H), 4.72 (m,1H), 3.69 (m, 3H), 3.53 (s, 2H), 3.23 (t, J=9.6 Hz, 2H), 2.80 (d, J=10.5Hz, 2H), 2.06 (m, 4H), 1.78-1.57 (m, 6H); LCMS (m/z): 619 (MH⁺).

Compound 146: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.41 (d, J=8.4 Hz, 1H), 7.99(s, 1H), 7.79 (t, J=4.5 Hz, 2H), 7.66 (m, 2H), 7.55 (d, J=7.5 Hz, 1H),7.46 (m, 3H), 7.06 (t, J=8.7 Hz, 3H), 4.73 (m, 1H), 3.69 (m, 2H), 3.64(s, 2H), 3.22 (m, 3H), 2.81 (d, J=10.5 Hz, 2H), 2.11 (m, 4H), 1.81-1.57(m, 6H); LCMS (m/z): 619 (MH⁺).

Compound 147: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.18 (d, J=7.8 Hz, 1H), 7.73(d, J=9.6 Hz, 2H), 7.47 (d, J=9.0 Hz, 2H), 7.19 (d, J=2.1 and 8.7 Hz,1H), 7.08 (d, J=8.7 Hz, 2H), 4.74 (m, 1H), 3.89 (d, J=12.6 Hz, 3H), 3.67(m, 2H), 3.23 (t, J=10.5 Hz, 3H), 2.89 (s, 2H), 2.06 (m, 2H), 1.82-1.70(m, 4H), 1.48 (m, 1H), 1.40 (s, 9H); LCMS (m/z): 638 (MH⁺).

Compound 148: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.84 (s, 1H), 8.70 (s, 1H),8.47 (d, J=6.9 Hz, 1H), 7.76 (m, 1H), 7.48 (d, J=8.7 Hz, 2H), 7.20 (d,J=9.0 Hz, 1H), 7.09 (d, J=9.0 Hz, 2H), 4.88 (m, 3H), 4.74 (m, 2H), 3.03(m, 1H), 3.68 (m, 2H), 3.25 (m, 3H), 3.01 (m, 1H), 2.02 (m, 3H), 1.77(m, 3H); LCMS (m/z): 538 (MH⁺).

Compound 149: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.51 (d, J=7.5 Hz, 1H), 7.96(s, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.47 (d, J=8.4 Hz, 3H), 7.13 (dd, J=2.4and 9.1 Hz, 1H), 7.07 (d, J=8.7 Hz, 2H), 4.69 (m, 1H), 3.93 (d, J=11.4Hz, 3H), 3.65 (s, 2H), 3.24 (m, 2H), 2.84 (m, 3H), 2.03 (m, 2H), 1.77(m, 4H), 1.47 (m, 1H), 1.41 (s, 9H); LCMS (m/z): 604 (MH⁺).

Compound 150: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.79 (d, J=7.5 Hz, 3H), 8.06(s, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.49 (m, 2H), 7.14 (dd, J=2.4 and 8.4Hz, 1H), 7.09 (d, J=9.3 Hz, 2H), 4.02 (m, 1H), 3.66 (m, 3H), 3.46 (m,1H), 3.28 (m, 3H), 3.00 (m, 2H), 2.03 (m, 4H), 1.75 (m, 4H); LCMS (m/z):504 (MH⁺).

Compound 151: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.48 (d, J=5.4 Hz, 2H), 8.15(d, J=7.8 Hz, 3H), 7.75 (d, J=2.1 Hz, 1H), 7.72 (s, 1H), 7.48 (d, J=9.0Hz, 2H), 7.30 (d, J=5.7 Hz, 2H), 7.18 (dd, J=1.8 and 8.8 Hz, 1H), 7.08(d, J=8.7 Hz, 2H), 4.74 (m, 1H), 3.70 (m, 3H), 3.50 (s, 2H), 3.22 (t,J=9.9 Hz, 2H), 2.76 (d, J=11.7 Hz, 2H), 2.10 (m, 4H), 1.81 (m, 2H), 1.65(m, 4H); LCMS (m/z): 629 (MH⁺).

Compound 152: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.45 (t, J=4.8 Hz, 2H), 8.14(d, J=7.2 Hz, 1H), 7.71 (m, 3H), 7.48 (d, J=8.4 Hz, 2H), 7.34 (t, J=6.6Hz, 1H), 7.18 (d, J=9.3 Hz, 1H), 7.08 (d, J=8.7 Hz, 2H), 4.73 (m, 1H),3.70 (m, 3H), 3.49 (s, 2H), 3.22 (t, J=9.6 Hz, 2H), 2.76 (d, J=10.5 Hz,2H), 2.07 (m, 4H), 1.79 (m, 2H), 1.72-1.59 (m, 4H); LCMS (m/z): 629(MH⁺).

Compound 153: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.46 (d, J=4.5 Hz, 1H), 8.15(d, J=7.8 Hz, 1H), 7.75 (m, 3H), 7.48 (d, J=9.0 Hz, 2H), 7.41 (d, J=7.5Hz, 1H), 7.22 (m, 2H), 7.08 (d, J=8.4 Hz, 2H), 4.74 (m, 1H), 3.70 (m,3H), 3.58 (s, 2H), 3.22 (t, J=9.3 Hz, 2H), 2.80 (d, J=10.8 Hz, 2H), 2.11(m, 4H), 1.84-1.58 (m, 6H); LCMS (m/z): 629 (MH⁺).

Compound 154: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.14 (d, J=7.8 Hz, 1H), 7.76(m, 4H), 7.48 (t, J=6.7 Hz, 4H), 7.18 (d, J=8.7 Hz, 1H), 7.08 (d, J=8.4Hz, 2H), 4.74 (m, 1H), 3.70 (m, 3H), 3.55 (s, 2H), 3.22 (t, J=9.0 Hz,2H), 2.73 (m, 2H), 2.10 (m, 4H), 1.80 (m, 2H), 1.65 (m, 4H); LCMS (m/z):653 (MH⁺).

Compound 155: ¹H NMR (DMSO-d₆, 300 MHz): δ 8.66 (d, J=3.6 Hz, 2H), 8.22(d, J=7.2 Hz, 1H), 7.74 (d, J=9.9 Hz, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.36(d, J=4.8 Hz, 2H), 7.19 (d, J=8.7 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 4.74(m, 1H), 4.36 (d, J=12.6 Hz, 2H), 4.07 (m, 1H), 3.70 (m, 2H), 3.45 (d,J=14.1 Hz, 1H), 3.22 (m, 3H), 3.04 (t, J=10.8 Hz, 1H), 2.06 (m, 2H),1.95 (m, 1H), 1.80-1.52 (m, 5H); LCMS (m/z): 643 (MH⁺).

(b) Assay Data

Compounds 137-141 and 143-155 of Table 1 were assayed for their abilityto activate AMPK using an enzyme-linked immunosorbent assay. The EC₅₀values for AMPK activation for compounds 137-141 and 143-155 arepresented in Table 5 below, in which “A” is less than 0.1 μM; “B” is0.1-0.5 μM; “C” is 0.5-1 μM; “D” is 1-50 μM and “F” is >50 μM:

TABLE 5 Cpd No. AMPK EC₅₀ 137 A 138 A 139 A 140 C 141 B 144 A 145 B 146B 147 D 148 F 149 A 150 D 151 A 152 A 153 B 154 A 155 A

Example 5 (a) Synthetic Example1-(4-fluorobenzyl)-N-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-yl)piperidin-4-amine(compound 159) Step 1.5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-one

To a stirred solution of 5-hydroxy-2,3-dihydro-1H-inden-1-one (0.74 g,5.0 mmol) in toluene (30 mL) at room temperature was added diisopropylazodicarboxylate (1.21 g, 6.0 mmol),1-(4-trifluoromethylphenyl)piperidin-4-ol (1.47 g, 6.0 mmol), andtriphenyl phosphine (1.57 g, 6.0 mmol). The mixture was stirred at 60°C. overnight and then concentrated under reduced pressure. The residueobtained was purified by flash chromatography (silica gel, ethylacetate/hexanes=1/1) to afford the title compound as a pale yellow solid(1.49 g, 79%). ¹H-NMR (CDCl₃, 300 MHz): δ 7.70 (m, 1H), 7.49 (m, 2H),6.93 (m, 4H), 4.65 (m, 1H), 3.59 (m, 2H), 3.30 (m, 2H), 3.09 (m, 2H),2.68 (m, 2H), 2.12 (m, 2H), 1.96 (m, 2H) ppm; MS (ESI): 376.6 (M+1).

Step 2. tert-butyl4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-ylamino)piperidine-1-carboxylate

Tert-butyl 4-aminopiperidine-1-carboxylate (0.48 g, 2.4 mmol) and5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-one(0.75 g, 2.0 mmol) were mixed in neat titanium(IV) isopropoxide (2.85 g,10.0 mmol) and stirred at room temperature overnight. Methanol (10 mL)was added followed by addition of sodium borohydride (0.12 g, 3.2 mmol).The reaction was stirred at room temperature for 3 h and then quenchedby adding 0.1N aqueous sodium hydroxide. The resulting mixture wasfiltered through celite, and the residue was washed with ethyl acetate(2×10 mL) and with dichloromethane (10 mL). The organic layer wasseparated and dried over sodium sulfate. The drying agent was filteredoff, and the filtrate concentrated under reduced pressure. The residueobtained was purified by flash chromatography (silica gel, ethylacetate/hexanes=1/4) to afford the title compound as a off-white solid(0.73 g, 65%). ¹H NMR (CDCl₃, 300 MHz) 7.64 (m, 1H), 7.48 (m, 2H), 6.95(m, 2H), 6.76 (m, 2H), 4.68 (m, 1H), 4.44 (m, 1H), 3.53 (m, 2H), 3.18(m, 2H), 2.85 (m, 4H), 2.47 (m, 2H), 2.24-1.79 (m, 12H), 1.46 (s, 9H)ppm; MS (ES) 560.6 (M+H).

Step 3.N-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-yl)piperidin-4-amine

A mixture of tert-butyl4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-ylamino)piperidine-1-carboxylate(0.73 g, 1.3 mmol) and 4N hydrochloric acid in dioxane (4 mL) wasstirred at room temperature for 1 h. The reaction mixture wasconcentrated and washed with diethyl ether (2×5 mL) and then dried underreduced pressure to afford the title compound (as the 3.HCl salt) as aoff-white solid (0.57 g, 97%). ¹H NMR (CD₃OD, 300 MHz) 7.73 (m, 2H),7.58 (m, 3H), 7.07 (s, 1H), 7.01 (m, 1H), 4.93 (m, 1H), 4.78 (m, 1H),3.65 (m, 6H), 3.20 (m, 5H), 2.62 (m, 1H), 2.35 (m, 6H), 2.08 (m, 5H)ppm; MS (ES) 460.7 (M+H)

Step 4.1-(4-fluorobenzyl)-N-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-yl)piperidin-4-amine

To a stirred mixture ofN-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-yl)piperidin-4-amine.3HCl(0.06 g, 0.1 mmol) in anhydrous dimethylformamide (0.5 mL) at roomtemperature was added 1-bromomethyl-4-fluorobenzene (0.02 g, 0.1 mmol)and N,N-diisopropylethylamine (0.07 g, 0.5 mmol). The resulting mixturewas stirred at room temperature overnight. After this time the mixturewas concentrated under reduced pressure and the resulting residue waspurified by flash chromatography (silica gel, methylenechloride/methanol/30% ammonium hydroxide=20/1/0.05) to afford the titlecompound as a off-white solid (0.05 g, 88%). ¹H NMR (CDCl₃, 300 MHz)7.46 (m, 2H), 7.25 (m, 3H), 6.96 (m, 4H), 6.75 (m, 2H), 4.47 (m, 1H),4.29 (m, 1H), 3.58 (m, 2H), 3.48 (s, 2H), 3.06-2.54 (m, 6H), 2.38 (m,1H), 2.14-1.74 (m, 9H), 1.49 (m, 2H) ppm; MS (ES) 568.6 (M+H).

(b) Analytical Data

The following compounds were prepared using methods analogous to thosedescribed in Example 5(a) and in Scheme 5.

Compound 156: ¹H NMR (CDCl₃, 300 MHz) δ 7.64 (m, 1H), 7.48 (m, 2H), 6.95(m, 2H), 6.76 (m, 2H), 4.68 (m, 1H), 4.44 (m, 1H), 3.53 (m, 2H), 3.18(m, 2H), 2.85 (m, 4H), 2.47 (m, 2H), 2.24-1.79 (m, 12H), 1.46 (s, 9H)ppm; MS (ES) 558.6 (M+H).

Compound 157: ¹H NMR (CD₃OD, 300 MHz) δ 7.73 (m, 2H), 7.58 (m, 3H), 7.07(s, 1H), 7.01 (m, 1H), 4.93 (m, 1H), 4.78 (m, 1H), 3.65 (m, 6H), 3.20(m, 5H), 2.62 (m, 1H), 2.35 (m, 6H), 2.08 (m, 5H) ppm; MS (ES) 460.7(M+H).

Compound 158: ¹H NMR (CDCl₃, 300 MHz) δ 8.53 (m, 2H), 7.62 (m, 1H), 7.46(m, 2H), 7.28 (m, 2H), 6.91 (m, 2H), 6.78 (m, 2H), 4.68 (m, 1H), 4.43(m, 1H), 3.52 (m, 4H), 3.17 (m, 2H), 2.84 (m, 4H), 2.46 (m, 2H),2.22-1.76 (m, 12H) ppm; MS (ES) 551.6 (M+H).

Compound 159: ¹H NMR (CDCl₃, 300 MHz) δ 7.46 (m, 2H), 7.25 (m, 3H), 6.96(m, 4H), 6.75 (m, 2H), 4.47 (m, 1H), 4.29 (m, 1H), 3.58 (m, 2H), 3.48(s, 2H), 3.06-2.54 (m, 6H), 2.38 (m, 1H), 2.14-1.74 (m, 9H), 1.49 (m,2H) ppm; MS (ES) 568.6 (M+H).

Compound 160: ¹H NMR (CDCl₃, 300 MHz) δ 7.60 (m, 2H), 7.45 (m, 4H), 7.22(m, 1H), 6.93 (m, 2H), 6.76 (m, 2H), 4.47 (m, 1H), 4.30 (m, 1H), 3.58(m, 4H), 3.23 (m, 2H), 2.99 (m, 1H), 2.79 (m, 6H), 2.39 (m, 1H),2.16-1.73 (m, 9H), 1.51 (m, 2H) ppm; MS (ES) 575.6 (M+H).

(c) Assay Data

Compounds 156-160 of Table 1 were assayed for their ability to activateAMPK using an enzyme-linked immunosorbent assay. The EC₅₀ values forAMPK activation for compounds 156-160 are presented in Table 6 below, inwhich “A” is less than 0.5 μM; “B” is 0.5-1 μM; “C” is 1-100 μM; and “D”is >100 μM:

TABLE 6 Cpd No. AMPK EC₅₀ 156 B 157 D 158 B 159 B 160 A

What is claimed is:
 1. A compound having the structural formula

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, orN-oxide thereof, wherein R¹ is H, —(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄alkyl); R² is —C(O)—O—(C₁-C₆ alkyl) or

in which each R¹⁵ is independently selected from —(C₁-C₃ alkyl), —(C₁-C₃haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN and two R¹⁵ on the same carbon optionally combineto form oxo; v is 0, 1 or 2; G is —CH₂—, —C(O)—, —S(O)₂— or —CH(CH₃)—;and R¹⁷ is aryl or heteroaryl, substituted with 1, 2 or 3 substituentsindependently selected from —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN; eachR³ is substituted on a benzo and is independently selected from —(C₁-C₃alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹,—(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN; w is 0, 1 or 2; each R¹⁴ is substituted on anon-benzo, non-pyrido carbon of the ring system denoted by “B”, and isindependently selected from —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN; k is0, 1 or 2; each R⁴ is independently selected from —(C₁-C₃ alkyl),—(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, and two R⁴ on the same carbon optionally combineto form oxo; x is 0, 1 or 2; Q is —CH₂—, a single bond, —C(O)—, —S(O)₂—or —CH(CH₃)—; the ring system denoted by “A” is heteroaryl or aryl; eachR⁵ is independently selected from —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl),—(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN; and yis 0, 1, 2 or 3; in which each L is independently selected from—NR⁹C(O)O—, —OC(O)NR⁹—, —NR⁹C(O)—NR⁹—, —NR⁹C(O)S—, —SC(O)NR⁹—,—NR⁹C(O)—, —C(O)—NR⁹—, —NR⁹C(S)O—, —OC(S)NR⁹—, —NR⁹C(S)—NR⁹—,—NR⁹C(S)S—, —SC(S)NR⁹—, —NR⁹C(S)—, —C(S)NR⁹—, —SC(O)NR⁹—, —NR⁹C(S)—,—S(O)₀₋₂—, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—,—SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—,—NR⁹C(NR²)NR⁹—, —NR⁹SO₂—, —SO₂NR⁹— and —NR⁹SO₂NR⁹—, each R⁷, R⁸ and R¹⁰is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl),—(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), each R⁹ is independently selected from —H,—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl).
 2. A compound according toclaim 1, having the structural formula


3. A compound according to claim 1, having the structural formula


4. A compound according to claim 1, wherein R¹ is H.
 5. A compoundaccording to claim 1, wherein R² is —C(O)—O—(C₁-C₆ alkyl).
 6. A compoundaccording to claim 1, wherein R² is


7. A compound according to claim 6, wherein v is
 0. 8. A compoundaccording to claim 6, wherein G is —CH₂— or —C(O)—.
 9. A compoundaccording to claim 6, wherein R¹⁷ is phenyl, pyridyl, pyrimidinyl orimidazolyl, each optionally substituted with 1, 2 or 3 substituentsindependently selected from —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN.
 10. Acompound according to claim 4, wherein R¹⁷ is phenyl optionallysubstituted with 1, 2 or 3 substituents independently selected from—(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN.
 11. A compound according toclaim 10, wherein v is 0 and G is —CH₂— or —C(O)—.
 12. A compoundaccording to claim 6, wherein R² is


13. A compound according to claim 12, wherein v is 0 and G is —CH₂— or—C(O)—.
 14. A compound according to claim 1, wherein w is
 0. 15. Acompound according to claim 1, wherein k is
 0. 16. A compound accordingto claim 1, wherein x is
 0. 17. A compound according to claim 1, whereinQ is a single bond.
 18. A compound according to claim 1, wherein Q is—CH₂—.
 19. A compound according to claim 1, wherein the ring systemdenoted by “A” is monocylic heteroaryl.
 20. A compound according toclaim 1, wherein the ring system denoted by “A” is phenyl.
 21. Acompound according to claim 1, having the structural formula

wherein G is —CH₂— or —C(O)— and R¹⁷ is phenyl, pyridyl, pyrimidinyl orimidazolyl, each optionally substituted with 1, 2 or 3 substituentsindependently selected from —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN; Q isa single bond or —CH₂—; the ring system denoted by “A” is phenyl; y is0, 1, 2 or 3; and each R⁵ is independently selected from —(C₁-C₃ alkyl),—(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN.
 22. A compound according to claim 1, having thestructural formula

wherein in which Q is —CH₂— or a single bond; G is a —CH₂— or —C(O)—:and R¹¹, R¹² and R¹³ are independently selected from H, halo, cyano,—(C₁-C₃ haloalkyl), —O—(C₁-C₂ haloalkyl), —(C₁-C₃ alkyl), —O—(C₁-C₂alkyl), —C(O)—(C₀-C₂ alkyl), —C(O)O—(C₀-C₂ alkyl), —C(O)N(C₀-C₄alkyl)(C₀-C₂ alkyl) and NO₂.
 23. A compound according to claim 1,wherein the compound is tert-butyl4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-ylamino)piperidine-1-carboxylate;1-(pyridin-4-ylmethyl)-N-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-yl)piperidin-4-amine;1-(4-fluorobenzyl)-N-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-yl)piperidin-4-amine;or4-((4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-ylamino)piperidin-1-yl)methyl)benzonitrile.24. A pharmaceutical composition comprising at least onepharmaceutically acceptable carrier, diluent or excipient; and acompound according to claim
 1. 25. A method for activating the AMPKpathway in a cell, the method comprising contacting the cell with aneffective amount of a compound according to claim
 1. 26. A method forincreasing fatty acid oxidation in a cell, the method comprisingcontacting the cell with an effective amount of a compound according toclaim
 1. 27. A method for decreasing glycogen concentration in a cell,the method comprising contacting the cell with an effective amount of acompound according to claim
 1. 28. A method for increasing glucoseuptake in a cell, the method comprising contacting the cell with aneffective amount of a compound according to claim
 1. 29. A method forreducing triglyceride levels in a subject, the method comprisingadministering to the subject an effective amount of a compound accordingto claim
 1. 30. A method for treating type II diabetes in a subject, themethod comprising administering to the subject an effective amount of acompound according to claim
 1. 31. A method for treating or preventingatherosclerosis or cardiovascular disease in a subject, the methodcomprising administering to the subject an effective amount of acompound according to claim 1.